@article {pmid41928210,
year = {2026},
author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V},
title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41928210},
issn = {1472-6963},
abstract = {OBJECTIVE: To evaluate the cost-utility of cerebrospinal fluid (CSF) and blood-based amyloid beta biomarkers for early detection of Alzheimer’s disease and mild cognitive impairment among older Thai adults at high risk of dementia.

METHODS: We constructed a decision tree with Markov models from a societal perspective, using a 1-year cycle over a lifetime horizon and applying a 3% annual discount. Amyloid beta (Aβ)1–42 was used for CSF, while Aβ40 and Aβ42 were used for blood. Sensitivity and specificity data were primarily derived from Thai patients at Siriraj Hospital, and nonpharmacological treatment efficacy was obtained from the FINGER study. Epidemiological data, transition probabilities, and costs were collected from the literature and Siriraj Hospital; direct nonmedical costs and utility values were also obtained from Siriraj. We calculated lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), evaluating cost-effectiveness against THB160,000 (USD4,370) per QALY. Parameter uncertainty was explored via sensitivity analyses. This is non-clinical trail study.

RESULTS: Compared with no testing, the CSF strategy yielded 0.011 additional life-years and 0.019 additional QALYs for an extra cost of THB2,589 (USD71), resulting in an ICER of THB132,961 (USD3,632) per QALY. Blood-based testing provided 0.009 additional life-years and 0.017 QALYs for an extra cost of THB15,467 (USD422), leading to an ICER of THB907,057 (USD24,776) per QALY.

CONCLUSIONS: CSF biomarker testing is cost-effective in Thailand, whereas blood-based biomarkers are not. Reducing the cost of Simoa (the technology used to measure blood biomarkers) by approximately 83% would improve the cost-effectiveness of blood-based biomarkers. Future research should enhance blood biomarker accuracy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14405-5.},
}

@article {pmid42125963,
year = {2026},
author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Frech, FH and Khachaturian, AS},
title = {Community-Based Physician Attitudes Related to the Diagnosis and Treatment of Early Alzheimer's Disease in the United States.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261433309},
doi = {10.1177/15333175261433309},
pmid = {42125963},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; United States ; Male ; Female ; *Attitude of Health Personnel ; *Neurologists/psychology ; *Cognitive Dysfunction/diagnosis/therapy ; *Physicians, Primary Care/psychology ; Middle Aged ; Early Diagnosis ; },
abstract = {The increasing incidence of Alzheimer's disease (AD) coupled with emerging diagnostics and treatments underscores the need for early detection of AD, yet identifying these individuals remains challenging. This US study sought to examine community-based physician attitudes regarding diagnosis and treatment of early AD (mild cognitive impairment [MCI] due to AD and mild AD). A total of 177 primary care physicians (PCPs) and 147 neurologists recruited through a national physician panel were surveyed about early AD diagnostic and treatment processes, and self-confidence in identifying and managing the condition. Physicians identified patient and family/caregiver involvement as critical in triggering the diagnostic process. Patterns of use of neurocognitive assessments, structural imaging tests, and AD-specific biomarkers varied between PCPs and neurologists. Confidence diagnosing and managing early AD was a concern across specialties, although was greater among PCPs. Programs promoting awareness of early AD symptoms, and emerging technologies and treatments are critical to timely management.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
United States
Male
Female
*Attitude of Health Personnel
*Neurologists/psychology
*Cognitive Dysfunction/diagnosis/therapy
*Physicians, Primary Care/psychology
Middle Aged
Early Diagnosis

@article {pmid42126808,
year = {2026},
author = {Taylor, TL and Tuke, J and Fernandez, EJ and Hazel, SJ},
title = {Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42126808},
issn = {2509-2723},
abstract = {Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer's disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.},
}

@article {pmid42127455,
year = {2026},
author = {Tzieras, I and Manolopoulos, A and Tweedie, D and Luo, W and Maccecchini, M and Egan, JM and Greig, NH and Kapogiannis, D},
title = {A phase 1, safety, tolerability, and pharmacokinetics study of bisnorcymserine, a highly selective inhibitor of butyrylcholinesterase.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00918},
doi = {10.1016/j.neurot.2026.e00918},
pmid = {42127455},
issn = {1878-7479},
abstract = {Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care

@article {pmid42129577,
year = {2026},
author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L},
title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71458},
pmid = {42129577},
issn = {1552-5279},
support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Neuropsychological Tests/statistics & numerical data ; Male ; *Cognitive Dysfunction/diagnosis ; Longitudinal Studies ; Biomarkers ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
Female
Aged
Neuropsychological Tests/statistics & numerical data
Male
*Cognitive Dysfunction/diagnosis
Longitudinal Studies
Biomarkers
Aged, 80 and over

@article {pmid42130250,
year = {2026},
author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I},
title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70903},
doi = {10.1002/jbt.70903},
pmid = {42130250},
issn = {1099-0461},
support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; Cell Line, Tumor ; *Neurons/metabolism/pathology/drug effects ; *Escin/pharmacology ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; NF-kappa B/metabolism ; Inflammation/metabolism ; },
abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Peptide Fragments/toxicity
Cell Line, Tumor
*Neurons/metabolism/pathology/drug effects
*Escin/pharmacology
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/metabolism/pathology/drug therapy
Cell Survival/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
NF-kappa B/metabolism
Inflammation/metabolism

@article {pmid42130609,
year = {2026},
author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S},
title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70259},
pmid = {42130609},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.},
}

@article {pmid42130762,
year = {2026},
author = {Liu, XY and Yan, YZ and Jiang, AJ and Tan, SJ and Fang, YY and Zeng, P},
title = {Integrating network pharmacology and experimental validation strategies to investigate the mechanisms and key flavonoids in medicinal and edible citrus plants against Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801263},
pmid = {42130762},
issn = {1663-4365},
abstract = {INTRODUCTION: Due to the complexity of the Alzheimer's disease (AD) pathophysiological processes, there is currently a lack of effective therapeutic drugs. The medicinal and edible substances have multiple advantages in treating AD, but their specific components and mechanisms remain unclear. This study aims to investigate the potential mechanisms of flavonoids in medicinal and edible citrus plants in treating AD and their key phytochemicals.

METHODS: We collected flavonoids identified by UHPLC-Q-TOF-MS/MS in citrus plants from the literatures and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the flavonoids of citrus plants and screened the targets related to AD key pathophysiological processes and the corresponding phytochemicals. The results of network pharmacological analysis were further validated through molecular docking, GEO database, and BV2 microglial cells.

RESULTS: A total of 51 flavonoids in medicinal and edible citrus plants were identified, which exhibit favorable pharmacological properties and safety profiles. Multiple flavonoid compounds such as isoquercitrin, astragalin, cynaroside, troxerutin and lonicerin serve as potential acetylcholinesterase inhibitors for the symptomatic treatment of AD. The study identified 45 flavonoids in citrus plants that correspond to 304 AD-related targets, which are involved in multiple pathophysiological processes. Quercetin, nobiletin, hesperidin, apigenin, HTMF, tangeretin and hesperetin have been identified as the key flavonoids of citrus plants that regulate the pathogenesis of AD in a multitargeted manner. The flavonoids of citrus plants primarily regulate the core targets AKT1, TNF, IL6, TP53, IL1B, STAT3, INS, JUN, CASP3 and CTNNB1. Targeting ferroptosis is one of the mechanisms by which citrus plants to ameliorate AD. In vitro experiments also demonstrated that hesperidin and naringin alleviated LPS-induced pro-inflammatory activation of BV2 cells.

CONCLUSION: The various citrus plants flavonoids examined in this study exhibit significant potential for clinical translation, particularly in the early prevention and adjuvant treatment of AD.},
}

@article {pmid42131436,
year = {2026},
author = {Gusmão, LA and Metzke, A and Deau, E and Meijer, L and Tedesco, AC and Köster, RW},
title = {Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.},
journal = {ACS applied nano materials},
volume = {9},
number = {18},
pages = {8023-8038},
pmid = {42131436},
issn = {2574-0970},
abstract = {A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.},
}

@article {pmid42133413,
year = {2026},
author = {Berezutsky, MA and Andronova, TA and Belonogova, YV and Durnova, NA},
title = {[Acteoside: neurobiological activity spectrum, potential in the treatment of age-associated neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {41-47},
doi = {10.17116/jnevro202612604141},
pmid = {42133413},
issn = {1997-7298},
mesh = {Humans ; *Glucosides/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Phenols/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects ; *Neurodegenerative Diseases/drug therapy ; Polyphenols ; },
abstract = {Acteoside (verbascoside, kusaginin) is a phenylethanoid glycoside, which is found in more than 200 species of plants and is characterized by a wide range of pharmacological activity. The results of studies on the neurobiological effects of acteoside, which can be used in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), were summarized and analyzed. The PubMed, Scopus, Google Scholar, and e-Library databases were searched for the following keywords: «acteoside», «Alzheimer's disease», «Parkinson's disease», «pathological activation of microglia», «neurotrophic effect», «endoplasmic reticulum stress», «protection of neurons from beta-amyloid», «inhibition of tau protein hyperphosphorylation», «death of dopaminergic neurons», «aggregation of α-synuclein», «cognitive and motor impairment». Experimental studies have shown the ability of acteoside to inhibit pathological activation of microglia, exert a neurotrophic effect, inhibit endoplasmic reticulum stress, protect neurons from beta-amyloid, inhibit tau-protein hyperphosphorylation, reduce intracellular Ca[2+] mobilization dysfunction, protect neurons from glutamate-induced neurotoxicity, prevent dopaminergic neuron death, reduce α-synuclein aggregation, and attenuate cognitive and motor impairments. This compound has good prospects for chemical modification, as its structure features several reactive sites. In the future, acteoside may be used as a multi-purpose complex therapy for AD and PD.},
}

Humans
*Glucosides/therapeutic use/pharmacology
*Parkinson Disease/drug therapy/metabolism
*Phenols/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Endoplasmic Reticulum Stress/drug effects
Animals
Amyloid beta-Peptides/metabolism
Microglia/drug effects
*Neurodegenerative Diseases/drug therapy
Polyphenols

@article {pmid42133414,
year = {2026},
author = {Shavlovskaya, OA},
title = {[Choline alfoscerate in the treatment of cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {48-55},
doi = {10.17116/jnevro202612604148},
pmid = {42133414},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Glycerylphosphorylcholine/therapeutic use/administration & dosage ; Alzheimer Disease/drug therapy ; Administration, Oral ; Injections, Intramuscular ; },
abstract = {Multiple randomized controlled trials (RCTs), systematic reviews, meta-analyses, and multidisciplinary studies in both hospital and outpatient settings have demonstrated the high efficacy and safety of choline alfoscerate (CA) therapy for patients with mild and moderate cognitive impairment (MCI), amnestic cognitive impairment, predementia cognitive impairment in Alzheimer's disease (AD), elderly individuals, and first-degree relatives of patients with AD as preventive therapy. The Russian CA drug Cereton is available in several formulations, including solutions for intravenous and intramuscular injection, capsules, and an oral solution, enabling individualized treatment approaches. In hospital settings, injection therapy with Cereton is administered for 10 days, followed by an oral course lasting up to 60 days. The duration and dosage of Cereton oral solution and capsules are determined by patient age and clinical condition. The oral solution is approved for use in children from 6 years of age, and the capsules are approved for use in children from 11 years of age, with treatment courses lasting up to 60 days. Cereton therapy consists of two stages: initial intravenous or intramuscular administration, followed by oral administration of capsules or the oral solution. The drug is generally well-tolerated, with adverse events being infrequent and minor.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Glycerylphosphorylcholine/therapeutic use/administration & dosage
Alzheimer Disease/drug therapy
Administration, Oral
Injections, Intramuscular

@article {pmid42133852,
year = {2026},
author = {Juni, JE and Burns, JM and Salat, DH and Hill, D and Tally, S and Martin, JS and Devous, MD and Moriarty, PM},
title = {Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261451918},
doi = {10.1177/15333175261451918},
pmid = {42133852},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; *Counterpulsation/methods ; Aged, 80 and over ; *Cognitive Dysfunction/therapy ; Treatment Outcome ; Activities of Daily Living ; },
abstract = {ObjectiveTo assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.MethodsThis 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.ResultsFull-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.ConclusionsFull-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.},
}

Humans
*Alzheimer Disease/therapy
Female
Male
Aged
*Counterpulsation/methods
Aged, 80 and over
*Cognitive Dysfunction/therapy
Treatment Outcome
Activities of Daily Living

@article {pmid41918005,
year = {2026},
author = {Singh, S and Sharma, Y and Bhardwaj, P and Kothari, D and Chhikara, A and Gupta, V and Kumar, D and Choudhary, N and Kondaveeti, SB},
title = {Next generation preventive neurology: how artificial intelligence and machine learning are reshaping Alzheimer's disease research.},
journal = {Behavioral and brain functions : BBF},
volume = {22},
number = {1},
pages = {},
pmid = {41918005},
issn = {1744-9081},
abstract = {UNLABELLED: A neurological condition that worsens over time, Alzheimer’s disease (AD) is typified by memory loss, cognitive decline, and functional degradation. Traditional diagnostic techniques such as neuroimaging, cerebrospinal fluid biomarkers, and neuropsychological testing are often intrusive, costly, or insensitive in the early stages. Recent years have seen the emergence of AI and ML as game-changing technologies for AD risk assessment, early detection, and customized prevention. Using sophisticated models such as deep learning, convolutional neural networks (CNNs), and graph-based algorithms, AI-driven methods achieve high performance: CNNs, for example, have reached diagnostic accuracies of 94–99% for early AD and mild cognitive impairment using multimodal MRI and PET data. However, most reported performance metrics are derived from retrospective analyses and internal validation cohorts, with limited external validation across diverse populations. These methods include multimodal data integration from neuroimaging, genetics, and clinical records. Years before symptoms appear, AI-based frameworks can predict disease progression, identify modifiable risk factors, and guide individualized treatment plans. Future developments in federated learning and explainable AI (XAI) are promising, although data privacy, algorithmic bias, and ethical ramifications are concerns. Overall, AI and ML have a great deal of promise to transform the prevention of AD, enabling precision therapy and enhancing the lives of those who are at risk.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid42116584,
year = {2026},
author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S},
title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.},
journal = {Protein and peptide letters},
volume = {33},
number = {1},
pages = {258-274},
doi = {10.2174/0109298665429866260217115717},
pmid = {42116584},
issn = {1875-5305},
mesh = {Humans ; *alpha-Synuclein/metabolism/genetics/antagonists & inhibitors ; *Synucleinopathies/metabolism/therapy/drug therapy/pathology ; *Parkinson Disease/metabolism/therapy/drug therapy/pathology ; Autophagy/drug effects ; Animals ; Oxidative Stress ; },
abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.},
}

Humans
*alpha-Synuclein/metabolism/genetics/antagonists & inhibitors
*Synucleinopathies/metabolism/therapy/drug therapy/pathology
*Parkinson Disease/metabolism/therapy/drug therapy/pathology
Autophagy/drug effects
Animals
Oxidative Stress

@article {pmid42116599,
year = {2026},
author = {Saha, T and Vats, T and Mehan, S},
title = {Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.},
journal = {Immunopharmacology and immunotoxicology},
volume = {},
number = {},
pages = {1-77},
doi = {10.1080/08923973.2026.2671714},
pmid = {42116599},
issn = {1532-2513},
abstract = {Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.},
}

@article {pmid42116632,
year = {2026},
author = {Han, KJ and Lv, YX and Xie, D and Zou, LH and Jiang, Q and Xie, SD and Zhang, YJ and Zhao, P and Yang, XQ and Wee, SK},
title = {Molecular Mechanistic Studies on Caffeoylquinic Acid Derivatives From Vaccinium dunalianum Wight as Dual-Target Inhibitors of AChE and BChE With In Vitro Inhibitory Evaluation and Molecular Docking.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {5},
pages = {e03013},
doi = {10.1002/cbdv.202503013},
pmid = {42116632},
issn = {1612-1880},
support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//National Natural Science Foundation of China/ ; 32060327//National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202505AO120060//Yunnan Foreign Expert Program/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; *Molecular Docking Simulation ; *Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; Animals ; Rats ; Structure-Activity Relationship ; PC12 Cells ; Plant Leaves/chemistry/metabolism ; Humans ; Dose-Response Relationship, Drug ; Molecular Structure ; Plant Extracts/chemistry/pharmacology ; Cell Survival/drug effects ; },
abstract = {Alzheimer's disease (AD) involves impaired cholinergic neurotransmission, so inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a major treatment strategy. Vaccinium dunalianum Wight leaf extracts, abundant in caffeoylquinic acids (CQAs), potently inhibit AChE (IC50 = 0.12 ± 0.01 mg/mL) and BChE (IC50 = 0.01 ± 0.01 mg/mL). Key bioactive compounds include 1-O-caffeoylquinic acid (1-CQA), chlorogenic acid (CGA), neochlorogenic acid (NCGA), and cryptochlorogenic acid (CCGA). All inhibited both enzymes concentration-dependently; 1-CQA was strongest (AChE IC50 = 0.25 ± 0.03 µM; BChE IC50 = 0.10 ± 0.01 µM), surpassing galantamine. Kinetics and docking showed reversible mixed-type inhibition targeting AChE catalytic and peripheral sites. Fluorescence quenching affirmed high-affinity binding, strongest for 1-CQA. It also showed low cytotoxicity in PC12 cells (≤10 µM). These findings reveal a dual cholinesterase inhibitory mechanism and support CQAs as promising anti-AD agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
*Molecular Docking Simulation
*Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification
*Acetylcholinesterase/metabolism
*Butyrylcholinesterase/metabolism
Animals
Rats
Structure-Activity Relationship
PC12 Cells
Plant Leaves/chemistry/metabolism
Humans
Dose-Response Relationship, Drug
Molecular Structure
Plant Extracts/chemistry/pharmacology
Cell Survival/drug effects

@article {pmid42118381,
year = {2026},
author = {S, K and L, G and S, PP and C, K},
title = {Aspirin as a neuroprotective scaffold in Alzheimer's disease: inflammation, oxidative stress, and future directions.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42118381},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Oxidative Stress/drug effects ; *Aspirin/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy ; Cyclooxygenase Inhibitors/pharmacology ; },
abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia. AD is associated with memory loss and cognitive decline. Several research works have been carried out to treat AD. However, currently available treatment options are only useful in the treatment of the individual pathology of AD but not useful in disease modification. Recent research works have identified the associated effects of neuroinflammation, oxidative stress, and glial cell dysfunction in AD pathology. Aspirin is one of the most commonly used NSAIDs in the treatment of several inflammatory diseases. Aspirin inhibits cyclooxygenase (COX) enzymes through an irreversible pathway. However, aspirin also exhibits other important pharmacological properties. This review aims to highlight the potential of aspirin-based multi-target directed ligands in the regulation of AD pathology through the regulation of neuroinflammation and oxidative stress.},
}

*Alzheimer Disease/drug therapy/metabolism
Oxidative Stress/drug effects
*Aspirin/pharmacology/therapeutic use
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Inflammation/drug therapy/metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use
Neuroinflammatory Diseases/drug therapy
Cyclooxygenase Inhibitors/pharmacology

@article {pmid42118396,
year = {2026},
author = {Kumar, R and Patel, S and Mishra, PS and Srivastava, S and Sridhar, SB and Shareef, J and Sahu, R and Tariq, M and Uddin, J and Muhsinah, AB},
title = {From Molecular Networks to Medicines: Targeting Complexity in Alzheimer's Disease (AD) Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42118396},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Molecular Targeted Therapy/methods ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multidimensional neurodegenerative disease leading to progressive loss of cognitive function and a growing health burden on the world population. Although decades of research have been conducted on this disease, current therapies have limited clinical value, mainly because researchers have not fully incorporated the intricate molecular pathways underlying its development and progression. This review summarizes current knowledge of AD pathophysiology, including amyloid beta (Aβ) dysregulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic breakdown. Although the amyloid- and tau-centered paradigms remain prevailing in the field, we note newer molecular targets, including secretase modulators, inflammatory signaling hubs, mitotic and autophagic regulators, epigenetics, and synaptogenesis pathways. We prioritize mechanistic, structural, cellular, and systems levels to facilitate a rational development of therapeutic understanding. The latest trends in medicinal chemistry and computational drug design, multi-target- directed ligands and hybrid scaffolds, as well as in silico ADMET optimization, are also discussed. Furthermore, we discuss the therapeutic aspects of bioinspired analogues of natural products. Lastly, we discuss the ongoing clinical development initiatives, opportunities, and major translational issues. In general, we highlight the need for integrative, mechanism-oriented, and personalized treatment approaches to propel the next generation of AD therapies.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Molecular Targeted Therapy/methods
Amyloid beta-Peptides/metabolism

@article {pmid42121268,
year = {2026},
author = {Cho, IH and Putra, HM and Jung, CW and Hyun, GH and Jang, HH and Hwang, IG and Kwon, SW},
title = {Neuroprotective effects of quercetin in animal models of neurodegenerative diseases: A systematic review and meta-analysis.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70699},
pmid = {42121268},
issn = {1097-0010},
support = {RS-2022-RD010385//Rural Development Administration/ ; },
abstract = {Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are characterized by progressive neuronal loss driven by oxidative stress and inflammation. Quercetin, a dietary flavonoid with established antioxidant and anti-inflammatory properties, has emerged as a potential neuroprotective agent. This study aimed to quantitatively synthesize and evaluate preclinical evidence regarding the impact of quercetin on neurodegenerative biomarkers and cognitive performance. A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). After strict screening and selection, 19 studies were included. These evaluated the effects of quercetin on: Morris water maze (MWM) performance; inflammatory cytokines - including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10); the oxidative stress marker malondialdehyde (MDA); antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH); brain-derived neurotrophic factor (BDNF); and acetylcholinesterase (AChE) activity. Subgroup analyses based on quercetin dose (<100 mg kg[-1] versus ≥100 mg kg[-1]) and treatment duration (<28 versus ≥28 days) were performed. Quercetin improved cognitive performance significantly by reducing escape latency and improving performance on memory retention indicators. It decreased pro-inflammatory cytokines (IL-6 and TNF-α), increased IL-10, enhanced antioxidant enzyme activity (CAT, SOD, and GSH), reduced MDA levels, up-regulated BDNF, and inhibited AChE. Subgroup analyses suggested that quercetin exerted stronger effects at lower doses and with longer treatment durations, although not all subgroup differences were statistically significant. Quercetin demonstrated multi-targeted neuroprotective effects in animal models, improving cognition and modulating inflammatory, oxidative, and neurotrophic pathways. These findings support the potential of quercetin as a therapeutic agent for neurodegenerative diseases, warranting further clinical investigation. © 2026 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42123478,
year = {2026},
author = {Xiao, Y and Huang, W and Chen, L and Huang, R and Guo, Y and Liu, W and Wang, X and Wang, J and Bao, J and Shu, X},
title = {Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093892},
pmid = {42123478},
issn = {1422-0067},
support = {82371195//National Natural Science Foundation of China/ ; 82001281//National Natural Science Foundation of China/ ; No. 2024HBQZYCSB046//Intelligent Cancer Prevention and Control Platform Development and Industrialization/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; Ferroportin ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Cation Transport Proteins/metabolism/genetics ; Mice ; Humans ; *Memory Disorders/metabolism/pathology ; *Brain/pathology/metabolism ; Mice, Transgenic ; Ferroptosis ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mutation ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
Ferroportin
*Amyloid beta-Protein Precursor/metabolism/genetics
*Cation Transport Proteins/metabolism/genetics
Mice
Humans
*Memory Disorders/metabolism/pathology
*Brain/pathology/metabolism
Mice, Transgenic
Ferroptosis
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mutation
Oxidative Stress

@article {pmid42125083,
year = {2026},
author = {Zhao, C and Peng, X and Cheng, Z and Yue, S and Wang, Z and Ma, L and Li, J and Shang, M},
title = {Light-based 40 Hz sensory therapy for brain disorders: physiological basis, therapeutic mechanisms, and future prospects.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1730333},
pmid = {42125083},
issn = {2296-858X},
abstract = {In recent years, 40 Hz flickering light and/or sound therapy has been confirmed to have certain therapeutic effects on Alzheimer's disease (AD), although the underlying mechanisms remain unclear. This approach has been widely explored for the treatment of various neurological disorders, but its efficacy must be verified. The induction of gamma oscillations in the brain by 40 Hz flickering light and/or sound stimulation is likely a critical component underlying its therapeutic effects across brain diseases. Elucidating the physiological basis and mechanisms by which such stimuli induce gamma oscillations may reveal its mechanisms of action in treating diseases. Although 40 Hz flickering light and/or sound intervention offers certain advantages in improving neurological function, challenges related to technical optimization and clinical promotion must be addressed. Therefore, in this paper, the underlying mechanisms through which 40 Hz flickering light and/or sound intervention induces gamma oscillations, including both neuronal and non-neuronal mechanisms, are explained. The clinical therapeutic outcomes of 40 Hz flickering light and/or sound intervention for various neurodegenerative diseases are subsequently examined, and the mechanisms underlying are summarized. Furthermore, the limitations of this therapy and corresponding improvement measures are discussed, providing a theoretical reference for further refining this technology and expanding its clinical applications. Finally, future development directions are provided, with the aims of advancing related research and facilitating the application of this therapy in the treatment of brain diseases.},
}

@article {pmid42111521,
year = {2026},
author = {Guo, B and Wang, J and Lou, F and Yuan, B and Chen, Z and Tang, C and Chen, W and Yi, F and Jiang, J and Hu, G and Cong, C and Lu, Y},
title = {Graphene field-effect transistor based multiplexed sensing platform for simultaneous detection of multiple Alzheimer's disease biomarkers.},
journal = {RSC advances},
volume = {16},
number = {26},
pages = {23937-23944},
pmid = {42111521},
issn = {2046-2069},
abstract = {Simultaneous detection of multiple biomarkers for one disease using a single drop of body fluid is challenging yet critical to confirm symptoms in the early stage. This study presents the development of a graphene field-effect transistor (GFET)-based multiplexed sensing platform designed for overcoming this obstacle. The platform utilizes a hexamethyldisilazane (HMDS) blocking layer as a hydrophobic treatment to enable recognition element (probe/aptamer) modifications within a small chip area (3 × 3 mm[2]), and this further enables simultaneous detection of multiple targets (multi-targets) in complex biological samples. The optimized aptamer/probe functionalization also enhances the specificity, sensitivity, and accuracy of the sensor. The technology was demonstrated with Alzheimer's disease (AD) biomarkers as a case study. Two distinctive biomarkers, hsa-miR-125b and Aβ42, are detected simultaneously with distinguishable signatures, and the lowest tested concentration is 1 fM. The cross-check experiments also show the effectiveness of the multi-target detection capability. This concise platform paves the way for accurate detection of early-stage diseases when the simultaneous identification of multiple biomarkers is required.},
}

@article {pmid42111940,
year = {2026},
author = {Ismail Al-Khaleel, R and Kalenahalli, Y and Hemalatha, S and Baker, S and Raj, SN and Rangappa, KS and Gowda, S and Siddaiah, C},
title = {Metabolomic analysis of Pennisetum glaucum seed extracts using advanced LC-MS/MS and Q-TOF technology.},
journal = {Journal of food science and technology},
volume = {63},
number = {5},
pages = {962-970},
pmid = {42111940},
issn = {0022-1155},
abstract = {UNLABELLED: Pearl millet (Pennisetum glaucum) is a cereal widely cultivated and grown in Africa and the Indian subcontinent for centuries. The present investigation aims to use LC-MS/MS to analyze the secondary metabolites present in pearl millet seeds using different solvents such as methanol, hexane, chloroform, and ethyl acetate. METLIN software was used to identify the metabolites. The analysis revealed the presence of 650 metabolites, among which 145 were commonly found in all the solvent extracts. The major classes of identified metabolites are terpenoids, flavonoids, sterols, amino acids, fatty acids, glycoconjugates, and carbohydrates. 80% methanolic extract and ethyl acetate extract yielded the highest concentrations of terpenoid (23%) and flavonoid (17%). The enrichment analysis was performed to statistically examine and identify the metabolites present in the metabolomic library dataset. In the hexane extract, notable metabolites such as quercetin and rutin were identified, which possess potential for the management of Alzheimer's disease due to their neuroprotective effects (p < 4e-35). In the methanol extract, metabolites like gallic acid and caffeic acid were associated with uremia treatment due to their antioxidant activity (p < 5e-37). Overall, the present study provides an overview of the metabolites present in the pearl millet seeds and the nutritive as well as therapeutic potential of these millets in the management of human diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-025-06328-6.},
}

@article {pmid42112453,
year = {2025},
author = {Usman, M and Ashebir, S and Okey-Mbata, C and Yun, Y and Kim, S},
title = {Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.},
journal = {Applied sciences (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {42112453},
issn = {2076-3417},
support = {SC1 NS122448/NS/NINDS NIH HHS/United States ; UG3 EB036466/EB/NIBIB NIH HHS/United States ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.},
}

@article {pmid42113681,
year = {2026},
author = {Wang, S and Yuan, X and Wang, T and Yang, M and Dong, P and Han, H},
title = {Mechanisms and Therapeutic Targeting of the GutMicrobiota-Immune-Brain Axis in Alzheimer's Disease.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-31},
doi = {10.1080/08820139.2026.2669375},
pmid = {42113681},
issn = {1532-4311},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease globally. The main pathological features of AD are amyloid-β (Aβ) deposition and tau hyperphosphorylation. Recent studies suggest that the gut microbiota-immunity-brain axis plays an important role in the onset and progression of AD. Gut microbiota dysbiosis may impair intestinal barrier integrity and promote the entry of pro-inflammatory mediators into the circulation. Pro-inflammatory signals in the bloodstream may further activate the central immune system, drive microglial polarization, and increase the release of inflammatory factors in the brain. The resulting neuroinflammatory cascade may aggravate Aβ accumulation, tau phosphorylation, and cognitive impairment, although this mechanism has not been conclusively established in humans.

METHODS AND RESULTS: Based on relevant literature on AD, gut microbiota, immunity, neuroinflammation, and the gut-brain axis, this article systematically reviews the mechanism of action of the microbiota-immunity-brain axis in AD. Current intervention strategies targeting this axis, including probiotics, fecal microbiota transplantation, dietary interventions, and traditional Chinese medicine, were also discussed. Such intervention measures have the potential to regulate the balance of the gut microbiota, reduce neuroinflammation, and slow the progression of AD pathology.

CONCLUSION: It is essential to integrate multi-omics approaches in future research to deepen the understanding of AD pathogenesis and support the development of more precise and personalized treatment strategies.},
}

@article {pmid42115432,
year = {2026},
author = {Ferré, CG and Pallàs, M and Franco, R},
title = {Molecular and statistical weaknesses of the p-tau217/Aβ1-42 plasma ratio for alzheimer's diagnosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42115432},
issn = {1432-1440},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; *Biomarkers/blood ; *Peptide Fragments/blood ; Reproducibility of Results ; },
abstract = {The FDA's approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio enhances access to Alzheimer's diagnostics but risks confusing convenience with biological accuracy. The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217/Aβ1-42 ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established. Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Amyloid beta-Peptides/blood
*tau Proteins/blood
*Biomarkers/blood
*Peptide Fragments/blood
Reproducibility of Results

@article {pmid42115835,
year = {2026},
author = {Fu, Q and Yin, X and Xu, S},
title = {Disentangling treatment status from disease severity in studies of diabetes and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71465},
doi = {10.1002/alz.71465},
pmid = {42115835},
issn = {1552-5279},
support = {824774630//National Natural Science Foundation of China/ ; 82274643//National Natural Science Foundation of China/ ; 20234Y0023//Shanghai Municipal Health Commission/ ; },
}

@article {pmid42116113,
year = {2026},
author = {Li, Y and Hu, C and Xia, C and Wang, X and Zhou, X and Xu, R and Li, Y and Mo, F and Zhao, B and Xu, L and Zhu, C and Chen, Z},
title = {A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04532-w},
pmid = {42116113},
issn = {1477-3155},
support = {202510315035//National Innovation and Entrepreneurship Training Program for Undergraduate/ ; 82304729//National Natural Science Foundation of China/ ; 82574587//National Natural Science Foundation of China/ ; BK20230457//Natural Science Foundation of Jiangsu Province/ ; ZYXYL2024-005//Scientific Research Foundation of Nanjing University of Chinese Medicine/ ; },
abstract = {The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as a drug delivery approach for the nose-brain pathway, offering valuable insights and prospects for enhancing AD treatment.},
}

@article {pmid42106468,
year = {2026},
author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C},
title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52291-3},
pmid = {42106468},
issn = {2045-2322},
support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; },
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.},
}

@article {pmid42107415,
year = {2026},
author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK},
title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {51-59},
doi = {10.1016/j.neurobiolaging.2026.04.009},
pmid = {42107415},
issn = {1558-1497},
abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid42107621,
year = {2026},
author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N},
title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.},
journal = {Experimental neurology},
volume = {403},
number = {},
pages = {115814},
doi = {10.1016/j.expneurol.2026.115814},
pmid = {42107621},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.},
}

@article {pmid42107748,
year = {2026},
author = {Suriyaamporn, P and Wongprayoon, P and Pannakkong, W and Pamornpathomkul, B and Ngawhirunpat, T and Rojanarata, T and Opanasopit, P},
title = {Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126967},
doi = {10.1016/j.ijpharm.2026.126967},
pmid = {42107748},
issn = {1873-3476},
abstract = {Progesterone (PG) is used to slow the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) in postmenopausal women. However, PG exhibits high lipophilicity, resulting in strong binding to skin tissues and plasma proteins, which may limit its systemic transport via transdermal routes. Solid lipid nanoparticles (SLNs) have been highlighted for their potential to enhance drug solubility and facilitate brain-targeted drug delivery for AD treatment. Microneedles (MNs) offer an advanced microtechnology for transdermal drug delivery, significantly improving drug permeation into the skin. However, traditional MNs fabrication methods face challenges related to shape control, dosage precision, high costs, and time consumption. Recent advancements in 3D printing technology offer a promising solution to these limitations. This study aimed to design and evaluate 3D-printed MNs-loaded with PG-SLNs for AD treatment. Biodegradable resin was utilized to fabricate MNs, aided by a Convolutional Neural Networks (CNNs) prediction model for improved accuracy. Mechanical strength, penetration efficiency, degradation, in vitro and in vivo drug delivery efficiency, cellular toxicity, and stability were evaluated. The optimized MNs, with a height of 756.98 ± 14.78 µm, effectively penetrated the skin barrier. SLNs exhibited a particle size of 308.91 ± 1.66 nm, PDI of 0.19 ± 0.08, and ZP of -30.03 ± 1.19 mV. The MNs retained sufficient mechanical strength post-drug loading, enabled efficient transdermal PG delivery, exhibited no cytotoxicity to neuronal cells, and remained physicochemically stable for up to 3 months. This study highlights the potential of 3D-printed MN patches as a novel transdermal drug delivery system, demonstrating practical feasibility for medical applications.},
}

@article {pmid42107892,
year = {2026},
author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H},
title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.},
journal = {International immunopharmacology},
volume = {182},
number = {},
pages = {116781},
doi = {10.1016/j.intimp.2026.116781},
pmid = {42107892},
issn = {1878-1705},
abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.},
}

@article {pmid42108759,
year = {2026},
author = {Meng, Q and Li, J and Xu, G and Zhang, W and Cao, R and Cai, K},
title = {Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis-Related Neuroinflammation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70860},
doi = {10.1002/jbt.70860},
pmid = {42108759},
issn = {1099-0461},
support = {YKK23216//Nanjing Health Science and Technology Development Special Fund/ ; ST222102//Major Sports Research Projects of Jiangsu Provincial Sports Bureau/ ; LKZ2025004//Jiangsu Elderly Health Scientific Research Project/ ; },
mesh = {Animals ; *Ginsenosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Ferroptosis/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; },
abstract = {Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.},
}

Animals
*Ginsenosides/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
Mice, Transgenic
Disease Models, Animal
*Ferroptosis/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
Male
Oxidative Stress/drug effects
Peptide Fragments

@article {pmid42109911,
year = {2026},
author = {Choi, S and Park, S and Jung, YH and Oh, MS and Yu, KH and Lee, BC and Lee, M},
title = {Comparative risk of dementia between direct oral anticoagulants and warfarin after atrial fibrillation related ischemic stroke.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1718536},
pmid = {42109911},
issn = {1663-4365},
abstract = {INTRODUCTION: Direct oral anticoagulants (DOAC) have been associated with a reduced risk of dementia compared to warfarin in patients with atrial fibrillation (AF) without prior stroke. However, the impact of DOAC on dementia risk in AF-related ischemic stroke survivors is unclear.

METHODS: We conducted a retrospective, nationwide cohort study using the Korean National Health Insurance Service database. We identified patients with newly diagnosed ischemic stroke and concurrent AF who began DOAC or warfarin therapy within one month after stroke. Incidence of all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) was compared between groups using multivariable Cox models with inverse probability of treatment weighting.

RESULTS: A total of 3,112 patients (mean age 70.6 ± 9.5 years; 66.6% male) were analyzed, including 2,919 DOAC users and 193 warfarin users. Over a mean follow-up of 3.63 years, 673 all-cause dementia cases (538 AD, 168 VaD) occurred. After IPTW, DOAC use was associated with higher risks of all-cause dementia (HR 1.16, 95% CI 1.04-1.30) and AD (HR 1.85, 95% CI 1.62-2.13) but a lower risk of VaD (HR 0.54, 95% CI 0.45-0.66) compared to warfarin.

DISCUSSION: In this retrospective nationwide cohort of AF-related ischemic stroke survivors, DOAC use was associated with a higher incidence of all-cause dementia and Alzheimer's dementia, but a lower incidence of vascular dementia, compared with warfarin. These observational findings suggest that anticoagulant type may be differentially associated with subsequent dementia subtypes in this high-risk population and should be interpreted with caution.},
}

@article {pmid42109914,
year = {2026},
author = {Fu, X and Huang, J and Liu, Y and Li, H and Zhang, Y},
title = {Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1797302},
pmid = {42109914},
issn = {1663-4365},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence, in which neuroinflammation serves as a critical pathological driver exacerbating cognitive decline. While current therapies offer limited symptomatic relief, multi-target strategies are urgently needed. Cervus cucumis polypeptide injection (CCPI), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-inflammatory properties; however, its mechanisms of action against AD remain unclear. This study aimed to elucidate the anti-AD potential mechanisms of CCPI using an integrated approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and experimental validation.

METHODS: Active components and corresponding targets of CCPI were retrieved from the TCMSP database, while AD-related targets were collected from Genecards, OMIM, and DrugBank. Potential therapeutic targets were identified by intersecting drug and disease targets, followed by protein-protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were performed to evaluate interactions between potential active components and key targets. In vitro experiments were conducted on Aβ25-35-induced BV2 microglial cells to assess cell viability (CCK-8 assay), inflammatory cytokine levels (ELISA), and protein expression (Western blot) related to the neuroinflammation pathway and microglial polarization.

RESULTS: A total of 28 active components and 50 common targets of CCPI for AD treatment were identified. Linoleic acid (LA) was determined to be a potential active component, with IL-6 as the key target based on PPI network topology. Molecular docking and MD simulation confirmed a stable binding affinity between LA and IL-6. KEGG analysis revealed significant enrichment in the HIF-1 signaling pathway, particularly the IL-6/STAT3/VEGF signaling pathway. In vitro, CCPI treatment significantly enhanced cell viability and attenuated the pro-inflammatory response, as evidenced by reduced levels of IL-6, IL-1β, and TNF-α, decreased the expression of the pro-inflammatory marker iNOS. Concurrently, it elevated the expression of the anti-inflammatory/repair-associated marker CD206. Western blot analysis further verified that CCPI suppressed IL-6/STAT3 activation while upregulating VEGF expression. Additionally, LA alone significantly reduced IL-6 levels and STAT3 phosphorylation, decreased the expression of iNOS, and increased the expression of CD206, with therapeutic efficacy comparable to CCPI.

CONCLUSION: CCPI exerts neuroprotective effects in AD models by regulating the IL-6/STAT3/VEGF pathway, downregulating the expression of the inflammation-related iNOS protein, upregulating the expression of the CD206 protein associated with anti-inflammatory and reparative functions, remodeling the functional state of microglia, inhibiting their pro-inflammatory responses, and enhancing their reparative functions. Its potential active component, LA, likely mediates this effect by stably binding to and inhibiting IL-6, thus suppressing the downstream STAT3 phosphorylation that drives inflammatory activation.},
}

@article {pmid42100782,
year = {2026},
author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T},
title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1727576},
pmid = {42100782},
issn = {1664-0640},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.},
}

@article {pmid42100836,
year = {2026},
author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S},
title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-55},
doi = {10.1017/neu.2026.10085},
pmid = {42100836},
issn = {1601-5215},
abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).},
}

@article {pmid42101516,
year = {2026},
author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W},
title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42101516},
issn = {1573-6903},
support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {PC12 Cells ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Amyloid beta-Peptides/metabolism ; *Polygala/chemistry ; *Calcium Signaling/drug effects/physiology ; *Nitric Oxide Synthase Type II/metabolism ; *Acorus/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.},
}

PC12 Cells
Animals
*Alzheimer Disease/drug therapy/metabolism
Rats
Amyloid beta-Peptides/metabolism
*Polygala/chemistry
*Calcium Signaling/drug effects/physiology
*Nitric Oxide Synthase Type II/metabolism
*Acorus/chemistry
*Plant Extracts/pharmacology/therapeutic use
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid42103387,
year = {2026},
author = {Laugesen, K and Skjærbæk, C and Okkels, N and Møller, HJ and Borghammer, P and Gottrup, H and Parkner, T},
title = {ODIN Biobank: a Danish cohort for dementia research- cohort profile.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e114084},
doi = {10.1136/bmjopen-2025-114084},
pmid = {42103387},
issn = {2044-6055},
mesh = {Humans ; Female ; Denmark ; Male ; Aged ; *Biological Specimen Banks ; *Dementia/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Alzheimer Disease/cerebrospinal fluid/blood ; Cognitive Dysfunction/cerebrospinal fluid/blood ; },
abstract = {PURPOSE: Biomarkers related to the diagnosis, prognosis and treatment of dementia will play a key role in future clinical practice. The overarching aim of the ODIN (blood and cerebrospinal fluid) Biobank is to study biomarkers for dementia and contribute to the transition from cerebrospinal fluid to blood-based biomarkers.

PARTICIPANTS: ODIN recruited 451 patients (median age 74 years, 53% females) referred to the Department of Neurology at Aarhus University Hospital, Denmark, for diagnostic assessment of dementia. Enrolment started in March 2020 and ended in July 2025. Patients referred for a lumbar puncture were eligible for inclusion. Cerebrospinal fluid and blood samples (plasma, serum and buffy coat) were stored at -80°C. Information about sociodemographic, educational level, dementia subtype, cognitive test scores, neuroimaging results, hypertension, diabetes, height, weight, alcohol consumption and smoking was collected.

FINDINGS TO DATE: The most frequent diagnoses were Alzheimer's disease (n=268, 59%), frontotemporal dementia (n=26, 5.8%) and mixed Alzheimer's and vascular disease (n=23, 5.1%). N=82 (18%) were cognitively unimpaired or had mild cognitive impairment but not dementia. The median Mini-Mental State Examination score was 23 (IQR: 20-26) and the median Addenbrooke's Cognitive Examination score was 68 (IQR: 58-77).

FUTURE PLANS: ODIN will contribute to the development, validation and implementation of new biomarkers related to diagnosis, prognosis and treatment of dementia. Furthermore, the cohort will assist the transition from cerebrospinal fluid to blood-based biomarkers.},
}

Humans
Female
Denmark
Male
Aged
*Biological Specimen Banks
*Dementia/cerebrospinal fluid/blood/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged, 80 and over
Cohort Studies
Middle Aged
Alzheimer Disease/cerebrospinal fluid/blood
Cognitive Dysfunction/cerebrospinal fluid/blood

@article {pmid42104655,
year = {2026},
author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN},
title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70436},
pmid = {42104655},
issn = {1471-4159},
support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; },
mesh = {Humans ; Female ; Aged ; *tau Proteins/blood ; Male ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *Sphingomyelins/blood ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cognition/physiology ; Cohort Studies ; },
abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.},
}

Humans
Female
Aged
*tau Proteins/blood
Male
*Alzheimer Disease/blood/diagnostic imaging/psychology
*Sphingomyelins/blood
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cognition/physiology
Cohort Studies

@article {pmid42105317,
year = {2026},
author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S},
title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2026.2669234},
pmid = {42105317},
issn = {1476-8305},
abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.},
}

@article {pmid42105452,
year = {2026},
author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z},
title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.},
journal = {Psychiatry research},
volume = {362},
number = {},
pages = {117212},
doi = {10.1016/j.psychres.2026.117212},
pmid = {42105452},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.},
}

@article {pmid42105933,
year = {2026},
author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, B and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ},
title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.05.006},
pmid = {42105933},
issn = {1878-7568},
abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.},
}

@article {pmid41906135,
year = {2026},
author = {Yang, R and He, Y and Pan, Y and Geng, A and Huang, F and Guo, K and Zhang, H},
title = {Multiparity exacerbates Aβ accumulation and promotes cellular senescence in a mouse model of amyloidosis.},
journal = {Immunity & ageing : I & A},
volume = {23},
number = {1},
pages = {},
pmid = {41906135},
issn = {1742-4933},
support = {82271472//the National Natural Science Foundation of China grants/ ; },
abstract = {BACKGROUND: Women have nearly twice the lifetime risk of Alzheimer’s disease (AD) as men. Hormonal and reproductive factors have been implicated; however, the role of parity, a female-specific experience, remains unknown. While epidemiological data suggest that high parity may increase the risk of dementia, the underlying biological mechanisms are unclear.

METHODS: We investigated the impact of multiparity on AD pathology using 2-month-old female 5xFAD mice. Mice were assigned to a nulliparous (0x) or multiparous (4x) (four consecutive gestation cycles) group. Brain tissues were analyzed at 6.4 months of age for Aβ pathology, neuroinflammation, synaptic markers, and senescence. Proteomic profiling and in vitro hormone treatment identified the key mediators. The role of voluntary running was assessed in a separate cohort of nulliparous mice.

RESULTS: Multiparous 5xFAD mice showed increased Aβ plaque burden, elevated BACE1 expression, synaptic loss, and activated senescence pathways compared to nulliparous controls. Proteomic analysis revealed sustained upregulation of the transcription factor FOSB. FOSB was found to drive BACE1 expression and Aβ production. In vitro co-treatment with estradiol and progesterone increased FOSB and BACE1 levels, supporting the presence of a hormone-responsive regulatory link. In nulliparous female 5xFAD mice, voluntary running from 2 to 6 months of age reduced Aβ deposition, fewer FOSB[+] neurons, and microglial activation compared with those in the sedentary controls.

CONCLUSIONS: Our findings identified the FOSB/BACE1 signaling axis as a link between reproductive history and AD pathology. Multiparity accelerates amyloid pathology and brain aging in female 5xFAD mice, mechanistically linked to hormone-driven FOSB upregulation. Physical activity downregulates this pathway in nulliparous animals. Whether exercise can mitigate parity-associated pathology remains to be investigated in multiparous animal models.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-026-00565-9.},
}

@article {pmid41913175,
year = {2026},
author = {Ito, K and Tsuda, S and Wake, T and Hatakeyama, A and Ogisawa, F and Ono, M and Nakayama, R and Wakui, T and Nagano, N and Iwata, A},
title = {Reframing dementia care in the era of disease-modifying therapies: informational, psychosocial, and systemic insights from Japan.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41913175},
issn = {1472-6963},
support = {25K14240//Grants-in-Aid for Scientific Research/ ; 25GB0301//Health and Labor Sciences Research Grant/ ; },
abstract = {BACKGROUND: The introduction of disease-modifying therapies (DMTs) for Alzheimer’s disease has prompted major changes in diagnostic pathways, referral processes, and service coordination in dementia care. Japan, as an early adopter of DMTs within a nationally coordinated dementia-care framework, offers an opportunity to examine how health service structures respond to these changes. This study explored health service–related support needs emerging across the DMT pathway, focusing on patient and informal caregiver experiences, with complementary perspectives from service providers.

METHODS: A qualitative study was conducted using semi-structured interviews with 48 participants, including nine patients who underwent DMT eligibility assessment, seven informal caregivers, 11 physicians, four nurses, five clinical psychologists, five social workers, and seven community-based dementia support providers. Data were analyzed using the Framework Method, an applied qualitative approach suitable for health services research. Patients’ and caregivers’ accounts were treated as the primary analytic focus, while provider perspectives were used to contextualize system-level factors influencing care delivery.

RESULTS: Three interrelated themes were identified. First, informational support needs reflected inequitable access to trustworthy information, difficulties in sustaining understanding of complex medical explanations, and a lack of structured opportunities to revisit information over time, particularly during transitions such as ineligibility, treatment discontinuation, or completion. Second, psychosocial support needs were closely shaped by service processes, including stigma-related experiences across clinical and social contexts, family-related tensions around treatment decisions, fluctuating expectations regarding treatment effects, and limited support for adjustment when DMT was no longer an option. Third, systemic and collaborative support needs highlighted fragmented roles between primary care and DMT-designated institutions, unclear referral and handover pathways, insufficient psychosocial care capacity, and weak integration between DMT delivery systems and existing dementia-care services.

CONCLUSIONS: The implementation of DMTs has amplified pre-existing gaps in dementia care systems, revealing previously underrecognized structural vulnerabilities across informational, psychosocial, and systemic domains. Findings indicate that DMTs should be embedded within coordinated care pathways that ensure continuity of information provision, access to psychosocial support, and clear allocation of follow-up responsibility regardless of treatment eligibility. Aligning pharmacological innovation with health service design is essential to support equitable, continuous, and person-centered dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14472-8.},
}

@article {pmid42100730,
year = {2026},
author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812975},
pmid = {42100730},
issn = {1662-4548},
abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.},
}

@article {pmid42097410,
year = {2026},
author = {Zhu, PF and Lyu, Z and Wang, Q and Li, S and Wang, X and Luo, A},
title = {ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108228},
doi = {10.1016/j.phrs.2026.108228},
pmid = {42097410},
issn = {1096-1186},
abstract = {Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.},
}

@article {pmid42097478,
year = {2026},
author = {Matošević, A and Maraković, N and Barić, D and Igert, A and Brazzolotto, X and Kovarik, Z and Bosak, A},
title = {Integrative Structural and Kinetic Analysis of the Molecular Basis for Reduced Carbamate Inhibition in Atypical Butyrylcholinesterase.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112134},
doi = {10.1016/j.cbi.2026.112134},
pmid = {42097478},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE) plays a key role in cholinergic transmission and the metabolism of various drugs, making its regulation a promising therapeutic strategy for several diseases, including Alzheimer's disease. Selective inhibition of BChE helps regulate brain acetylcholine levels. However, genetic polymorphisms in the BCHE gene, particularly the Asp70Gly mutation in atypical BChE, can impact treatment outcomes. This study compares the inhibitory potency of 13 carbamates against atypical and usual BChE. Using molecular docking, quantum chemical cluster calculations, and crystallization of wild-type BChE with the most potent carbamate, we identified key differences in carbamylation mechanisms. Atypical BChE shows a less favorable enzyme-inhibitor complex orientation, lacking the hydrogen bond stabilization of the reactive carbonyl oxygen. Additionally, Asp70 in usual BChE contributes to stabilizing the non-reactive carbamate group, whereas Gly70 in atypical BChE is too distant to form such interactions.},
}

@article {pmid42097853,
year = {2026},
author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM},
title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9395},
pmid = {42097853},
issn = {1936-959X},
abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.},
}

@article {pmid42098313,
year = {2026},
author = {Shinagawa, S and Onuki, K and Shimizu, K},
title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51118-5},
pmid = {42098313},
issn = {2045-2322},
support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; },
abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.},
}

@article {pmid42098771,
year = {2026},
author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I},
title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02928-7},
pmid = {42098771},
issn = {1478-811X},
abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.},
}

@article {pmid42099124,
year = {2026},
author = {Cheng, B and Wei, W and Cheng, S and Yang, X and Pan, C and He, D and Feng, J and Zhang, F},
title = {Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-8},
doi = {10.1192/bjp.2026.10638},
pmid = {42099124},
issn = {1472-1465},
abstract = {BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear.

AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression.

METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use.

RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases.

CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.},
}

@article {pmid42099163,
year = {2026},
author = {Li, Y and Li, L and Yang, Q and Xiong, J},
title = {Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050437623260417063631},
pmid = {42099163},
issn = {1875-5828},
abstract = {INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability.

METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated.

RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits.

DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease.

CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.},
}

@article {pmid42099165,
year = {2026},
author = {Yang, Y and Huang, X and Liu, H and Yu, C},
title = {The Role of Ectopic Fat in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050461650260406064722},
pmid = {42099165},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder increasingly recognized to be associated with metabolic dysfunction. Accumulating evidence suggests that ectopic fat (abnormal fat deposition in non-adipose tissue) is a key factor. This review summarizes the crucial role that ectopic fat plays in the onset and progression of AD, as well as the interrelated pathways through which ectopic fat deposition promotes the pathological process of AD. Adipocytes have been reported to produce and secrete amyloid-β (Aβ), a hallmark pathological feature of AD. Accordingly, ectopic fat may aggravate cerebral Aβ accumulation by impairing peripheral Aβ clearance. In addition, ectopic fat can also cause Insulin Resistance (IR), adipokine dysregulation, inflammatory responses, and oxidative stress. Therefore, ectopic fat is closely associated with the progression of AD and may play a contributory role in its pathogenesis. The effects of ectopic fat on the occurrence and development of Alzheimer's Disease (AD) pathology were reviewed through mechanisms such as metabolic disorders, inflammatory pathways, and Aβ deposition, and potential intervention strategies for this harmful cycle were highlighted. As current therapies for AD remain limited, new opportunities for its prevention and treatment may be provided through a better understanding of these associations.},
}

@article {pmid42100482,
year = {2026},
author = {Zhao, H and Wang, H and Li, W and Su, R and Li, J and Liu, Y and Wang, L},
title = {Integrated transcriptomic profiling combined with in vitro validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761218},
pmid = {42100482},
issn = {1663-4365},
abstract = {OBJECTIVE: Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and in vitro RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.

METHODS: Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the in vitro experiments, a Porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.

RESULTS: Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. In vitro experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked upregulation of IL-1β, IL-6, TNF-α, p16, p21, RELA, NFKBIA, and TP53, indicating that reduced TMEM140 expression may contribute to enhanced susceptibility of neuron-like cells to inflammatory stress.

CONCLUSION: Through integrated transcriptomic analysis together with in vitro experimental validation, this study indicates that TMEM140 may be a candidate bridge molecule connecting PD and AD comorbidity. TMEM140 may participate in shaping the peripheral-central immunosenescence network and contribute to the cross-system transmission of inflammatory signaling.},
}

@article {pmid41896988,
year = {2026},
author = {Ma, Y and Xie, M and Ibáñez, CF},
title = {Palmitoylation of death receptor p75[NTR] contributes to Alzheimer's disease progression by regulating APP trafficking and degradation.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896988},
issn = {1758-9193},
abstract = {UNLABELLED: Although protein palmitoylation has been associated with Alzheimer’s Disease (AD), it remains unclear whether or how palmitoylation of specific proteins contributes to any of the pathological features of AD. The p75 neurotrophin receptor (p75[NTR]) contributes to AD progression by regulating the intracellular trafficking and amyloidogenic processing of amyloid precursor protein (APP). p75[NTR] is palmitoylated at a juxtamembrane cysteine but it is currently unknown whether this has any effect on its role in AD. Here, we report that 5xFAD mice, an animal model of AD, expressing a palmitoylation-deficient mutant of p75[NTR] (p75[C281A]) display significantly attenuated neuropathology and cognitive deficits. Mechanistically, p75[C281A] showed enhanced internalization, trafficking to Rab5/Rab7 endosomes and lysosomal-mediated degradation. In mutant p75[C281A] neurons, APP displayed accelerated co-internalization with p75[NTR], increased trafficking to late endosomes and lysosome, and enhanced degradation, thereby limiting neuronal Aβ production. Interestingly, the brain of 5xFAD mice shows increased levels of p75[NTR] palmitoylation. These results indicate that palmitoylation of p75[NTR] enhances its stability and, indirectly, that of APP by reducing their trafficking to the lysosome, resulting in increased Aβ accumulation and neuropathology in the AD brain. Selective inhibitors of p75[NTR] palmitoylation may find applications in the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02032-5.},
}

@article {pmid41896998,
year = {2026},
author = {van der Schaar, J and van der Flier, WM and Visser, LNC and van de Giessen, E and van Harten, AC and Sikkes, SAM and van Leeuwenstijn-Koopman, MSSA and Hendriksen, HMA and Trieu, C and Bredenoord, AL and van den Hoven, MA and Asscher, ECA},
title = {Long-term impact of disclosing amyloid PET results to individuals with subjective cognitive decline.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896998},
issn = {1758-9193},
support = {LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; LSHM20106//∼Holland, Topsector Life Sciences & Health/ ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Biomarker assessments increasingly inform the diagnostic evaluation and treatment decisions in Alzheimer disease (AD). However, evidence on the impact of amyloid positron emission tomography (PET) disclosure is primarily derived from studies of cognitively unimpaired trial participants with follow-up limited to 18 months. In contrast, long-term implications for individuals with cognitive concerns who seek medical evaluation in memory clinics remain unknown. We aimed to examine the psychosocial and behavioral impact three years after amyloid PET disclosure in individuals presenting with subjective cognitive decline (SCD) at a memory clinic.

METHODS: In-depth semi-structured interviews were conducted with 17 participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (67 ± 7 years; 5 female; 10 amyloid positive) 35 ± 4 months post-disclosure. All had SCD at imaging; one had progressed to mild cognitive impairment (MCI) at interview. Verbatim transcripts were analyzed inductively.

RESULTS: Participants’ motivations for testing and long-term adaptation to the results were strongly shaped by cognitive concerns and personal experiences of dementia in relatives. All demonstrated accurate comprehension of their amyloid status. Those with negative scans described immediate relief and reattributed memory lapses to normal aging, while recognizing that the reassurance was provisional. Although positive scans provoked initial shock and fear of deterioration, participants valued information over uncertainty, and over time, fear attenuated as they perceived no rapid decline. Both groups regarded results as meaningful and personally actionable, informing health behavior, life priorities, and preparations for future decline. Fourteen of 17 participants spontaneously mentioned considering options for self-determined end-of-life. Regardless of amyloid status, most participants shared their result with close relatives and friends, some also informed colleagues or acquaintances, while others limited communication to avoid stigma, protect loved ones, or reduce the burden of repeated explanations. Participants valued testing, expressed no regret, and would choose disclosure again.

CONCLUSIONS: Three years after disclosure, participants generally had adjusted to living with their imaging result, finding personal meaning and practical engagement without reporting ongoing psychological harm. Some reported residual concerns and uncertainty, irrespective of amyloid status. These findings offer timely guidance for clinicians and patients as biomarker disclosure is more widely incorporated into routine practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02026-3.},
}

@article {pmid42089987,
year = {2026},
author = {Chen, S and Zhao, K and Shi, Z and Zhang, C and Wu, H and Tian, M and Sun, Y and He, L},
title = {Study on the improvement effect and mechanism of resveratrol on cognitive impairment in tau mutant adenovirus-induced alzheimer's disease model mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42089987},
issn = {1432-2072},
abstract = {RATIONALE: Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood.

OBJECTIVES: To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation.

METHODS: Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays.

RESULTS: RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators.

CONCLUSIONS: RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.},
}

@article {pmid42090736,
year = {2026},
author = {Malotaux, V and Ku, V and Ospina Lopera, P and Su, Y and Chen, Y and Singh, A and Ruiz-Triviño, J and Hidalgo, MJ and Osorio, L and Serna, L and Giraldo, D and Alzate, D and He, B and Tristão-Pereira, C and Ramirez Gomez, L and Do Carmo, S and Cuello, AC and Ashton, NJ and Reiman, EM and Aguillón, D and Quiroz, YT},
title = {Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100578},
doi = {10.1016/j.tjpad.2026.100578},
pmid = {42090736},
issn = {2426-0266},
abstract = {BACKGROUND: Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.

OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.

DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.

PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).

MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.

RESULTS: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.

CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.},
}

@article {pmid42090785,
year = {2026},
author = {Sánchez Valle, R and Lleó Bisa, A and Villarejo Galende, A and Cuartero Rodríguez, E and Escudero-Torrella, J and Bargallo Alabart, N},
title = {Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100586},
doi = {10.1016/j.tjpad.2026.100586},
pmid = {42090785},
issn = {2426-0266},
abstract = {BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.

OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.

This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.

MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.

RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.

CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.},
}

@article {pmid42091766,
year = {2026},
author = {Kumar, V and Kakoty, V and Wadhwa, P},
title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42091766},
issn = {1559-1182},
mesh = {*Alzheimer Disease/therapy/genetics ; *Nanoparticles/chemistry/administration & dosage ; Humans ; *Gene Transfer Techniques ; Animals ; *Nucleic Acids/administration & dosage ; *Genetic Therapy/methods ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.},
}

*Alzheimer Disease/therapy/genetics
*Nanoparticles/chemistry/administration & dosage
Humans
*Gene Transfer Techniques
Animals
*Nucleic Acids/administration & dosage
*Genetic Therapy/methods
Brain/metabolism

@article {pmid42091792,
year = {2026},
author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C},
title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42091792},
issn = {2190-3948},
support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; },
abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.},
}

@article {pmid42093461,
year = {2026},
author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH},
title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2667432},
pmid = {42093461},
issn = {1758-2032},
abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.},
}

@article {pmid42094385,
year = {2026},
author = {Sanders, B and Korthauer, M and Singh Parihar, K and Ifergan, I},
title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.720934},
pmid = {42094385},
issn = {2692-8205},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12 [+] microglial populations, particularly the CD11c [+] subset, and comparatively limited sustained effects in CD11b [+] P2RY12 [-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42094534,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose improves cognitive function in a mouse model of normal aging but not Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.28.721469},
pmid = {42094534},
issn = {2692-8205},
abstract = {INTRODUCTION: Declines in function occur in both normal aging (in the absence of disease) and age-related pathological contexts, like Alzheimers disease (AD). Whether anti-aging interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid42094538,
year = {2026},
author = {Woodham, TA and Kelsey, MMG and Sedivy, JM},
title = {Characterization of Cellular Senescence in Primary Human Astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721581},
pmid = {42094538},
issn = {2692-8205},
abstract = {Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.},
}

@article {pmid42095064,
year = {2026},
author = {Cummings, JL and Zhou, Y and Yang, Y and Zhong, K and Fonseca, J and Osse, AL and Cheng, F},
title = {Alzheimer's disease drug development pipeline: 2026.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70251},
pmid = {42095064},
issn = {2352-8737},
abstract = {INTRODUCTION: Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.

RESULTS: There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.

DISCUSSION: The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.},
}

@article {pmid42095076,
year = {2026},
author = {Sajan, MP and Aggarwal, G and Hwang, JJ and Smith, DM and Cooper, DR and Duncan, MA and Hansen, BC and Nguyen, AD and Farese, RV},
title = {Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115720},
pmid = {42095076},
issn = {2589-0042},
abstract = {Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.},
}

@article {pmid42095886,
year = {2026},
author = {Maiese, K},
title = {Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, wnt, and WISP1.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2671269},
pmid = {42095886},
issn = {1751-2441},
abstract = {INTRODUCTION: Increased global lifespan is paralleled by a rise in non-communicable diseases with osteoarthritis and dementia, including Alzheimer's disease, impacting all nations with severe disability, death, and financial burden.

AREAS COVERED: Given that osteoarthritis and dementia are worsened with advancing age, progressive in nature, and presently remain only with symptomatic treatments, development of advanced comprehensive therapies is critical for these disorders. New innovative work offers insight into the underlying clinical bond between degenerative joint disease and cognitive loss. Data sources using systematic literature search employed PubMed, Scopus, Web of Science, and ScienceDirect from January 2021 through February 2026.

EXPERT OPINION: Although affecting diverse organ systems, degenerative joint disease and dementia are intimately connected by shared cellular pathways responsible for disease onset and progression. Pioneering avenues of investigation of oxidative stress, autophagy, the mechanistic target of rapamycin (mTOR), cellular metabolism mechanisms with glucagon-like peptide-1 (GLP-1) receptors and AMP activated protein kinase (AMPK), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) offer exciting treatment opportunities for osteoarthritis and Alzheimer's disease. Ultimately, these complex pathways will necessitate focus upon their intricate dependence that may benefit from several targeted approaches including artificial intelligence applications for fruitful clinical translation.},
}

@article {pmid42096531,
year = {2026},
author = {Uchida, H and Gobbi, G and Zohar, J and Young, AH and Rujescu, D and Huang, MC and Sundram, S and Atwoli, L and Vukovic, J and Ikeda, K},
title = {Global Perspectives on CNS Drug Innovation: Achievements, Barriers, and Priorities for the Next Decade.},
journal = {The international journal of neuropsychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijnp/pyag023},
pmid = {42096531},
issn = {1469-5111},
abstract = {BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.

METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.

RESULTS: Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.

CONCLUSIONS: To convert momentum into durable progress, we recommend: (i) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments and non-for profit foundations; (ii) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (iii) data-driven development integrating RWE, AI/ML, and precision medicine; (iv) the adoption of Neuroscience-based Nomenclature (NbN); and (v) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.},
}

@article {pmid42097044,
year = {2026},
author = {Shu, Y and Ding, ZH and Chen, XQ and Liu, F},
title = {40 Hz light flicker stimulation for neurodegenerative diseases: Mechanisms and clinical perspectives.},
journal = {Biochemical and biophysical research communications},
volume = {821},
number = {},
pages = {153858},
doi = {10.1016/j.bbrc.2026.153858},
pmid = {42097044},
issn = {1090-2104},
abstract = {Neurodegenerative diseases are a class of disorders characterized by the progressive degeneration and dysfunction of neurons, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Due to their high incidence rate, irreversible pathological processes and huge social and economic burdens, these diseases have become a major challenge in global public health. Light Flicker Stimulation (LFS), as a non-invasive form of physical therapy, shows significant neuroprotective potential by modulating electrical brain oscillations and particular signaling pathways. We critically examine the role of stimulation parameters (frequency, wavelength, multisensory combination) and discuss the state of clinical translation, including completed and ongoing trials, safety considerations, and technological innovations such as alternating bilateral stimulation and organic light-emitting diode (OLED) devices. By integrating mechanistic insights with clinical perspectives, this review aims to identify key gaps and future directions for harnessing 40 Hz LFS as a viable treatment for neurodegenerative diseases.},
}

@article {pmid42097270,
year = {2026},
author = {Cho, E and Lee, S and Lee, H and Kim, J and Kwon, YW and Hoe, HS and Kim, D and Yoon, JH},
title = {An integrative proteomic approach to reveal altered signaling modules during Alzheimer's disease progression in PS19 tauopathy mice.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101580},
doi = {10.1016/j.mcpro.2026.101580},
pmid = {42097270},
issn = {1535-9484},
abstract = {Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.},
}

@article {pmid42097395,
year = {2026},
author = {Shahsavari, F and Rajizadeh, MA and Pirmoradi, Z and Sabzalizadeh, M and Kohlmeier, KA and Soti, M and Shabani, M},
title = {Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138619},
doi = {10.1016/j.neulet.2026.138619},
pmid = {42097395},
issn = {1872-7972},
abstract = {Abscisic acid (ABA, C15H20O4), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ1-42 in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ1-42 administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.},
}

@article {pmid42083975,
year = {2026},
author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP},
title = {Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Cerebral Hypoperfusion & Mild Cognitive Impairment at 2 months of age.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00711.2025},
pmid = {42083975},
issn = {1522-1539},
support = {5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; },
abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20[th] week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n=22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 months of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n=4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.},
}

@article {pmid42083983,
year = {2026},
author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A},
title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42083983},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.},
}

@article {pmid42084750,
year = {2026},
author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA},
title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42084750},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuropharmacology/trends/methods ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuropharmacology/trends/methods
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid42084972,
year = {2026},
author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A},
title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.},
journal = {Indian journal of public health},
volume = {},
number = {},
pages = {},
doi = {10.4103/ijph.ijph_102_25},
pmid = {42084972},
issn = {0019-557X},
abstract = {Diabetes mellitus (DM) affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence. This review explores the various aspects of DM and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for DM and to understand the challenges faced in making novel therapies. It is also needed to recognise the intricate relationship between diabetes and Alzheimer's disease, an emerging entity known as type 3 diabetes. Literature search was done in PubMed database, and relevant articles were selected for the narrative review. The review reveals that currently, most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. There are evidences to support that Alzheimer's disease can rightly be called type 3 diabetes. In conclusion, there is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.},
}

@article {pmid42086977,
year = {2026},
author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D},
title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42086977},
issn = {2190-3948},
abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.},
}

@article {pmid42087592,
year = {2026},
author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L},
title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.},
journal = {Developmental neurobiology},
volume = {86},
number = {3},
pages = {e70034},
doi = {10.1002/dneu.70034},
pmid = {42087592},
issn = {1932-846X},
support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism/genetics ; *POU Domain Factors/metabolism/genetics ; *Homeodomain Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; },
abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.},
}

Animals
Humans
*Brain/growth & development/metabolism
*Mental Disorders/metabolism/genetics
*POU Domain Factors/metabolism/genetics
*Homeodomain Proteins/metabolism
*Nerve Tissue Proteins/metabolism

@article {pmid42088060,
year = {2026},
author = {Hou, DL and Ho, J and Guan, T and Dong, XX and Zeng, L and Sanders, LH and Wu, YC and Tan, EK and Zhou, ZD},
title = {E3 ubiquitin ligases in neurodegenerative diseases.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100032},
pmid = {42088060},
issn = {2054-9369},
mesh = {Humans ; *Ubiquitin-Protein Ligases/therapeutic use ; *Neurodegenerative Diseases/physiopathology ; },
abstract = {Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, trans-active response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.},
}

Humans
*Ubiquitin-Protein Ligases/therapeutic use
*Neurodegenerative Diseases/physiopathology

@article {pmid42089471,
year = {2026},
author = {Shu, D and Fu, C and Liu, Z and Li, C},
title = {The role of Annexin A2 in Alzheimer's disease: From cellular functions to therapeutic potential.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70574},
pmid = {42089471},
issn = {1742-4658},
support = {31900692//National Natural Science Foundation of China/ ; 32070961//National Natural Science Foundation of China/ ; 2024AFB558//Natural Science Foundation of Hubei Province/ ; },
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder with a rising global prevalence, is pathologically characterised by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). These lesions lead to synaptic damage, neuronal loss, and cognitive impairment. Despite the recent approval of immunotherapies for AD treatment, their limited efficacy highlights the urgent need for exploring novel disease mechanisms and developing targeted therapeutic strategies. Annexin A2 (ANXA2), a calcium-dependent phospholipid-binding protein, participates in diverse physiological processes (e.g. membrane organisation, cytoskeleton linkage) and contributes to the pathogenesis of diseases such as cancer and Parkinson's disease. Emerging evidence indicates that ANXA2 interacts with AD-related pathological components (Aβ, tau) and regulates AD-associated inflammatory pathways, suggesting its potential role in AD. However, current evidence regarding ANXA2 in AD remains limited, and the molecular mechanisms underlying its contribution to AD pathogenesis remain unclear. This review comprehensively summarises the current knowledge on ANXA2's cellular and physiological functions in the central nervous system (CNS), as well as its involvement in AD pathology, aiming to provide guidance for research into ANXA2's therapeutic potential for AD prevention and treatment.},
}

@article {pmid42089534,
year = {2026},
author = {Liang, S and Lapane, KL and Ott, BR and Tjia, J and Baek, J and Yuan, Y and Alcusky, M},
title = {Antidepressant Use Among US Nursing Home Residents With Dementia.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70492},
pmid = {42089534},
issn = {1532-5415},
support = {5R01AG068450-03/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: In 2024, 6.9 million Americans lived with Alzheimer's disease and related dementias (ADRD), with nursing homes serving as a major site of care. Antidepressants are the most prescribed psychotropic medications among nursing home residents with ADRD, yet detailed information on prescribing patterns, potential indications, and associated resident and facility characteristics remain limited.

METHODS: Using 2018 minimum data set 3.0 assessments linked to Medicare claims, we conducted a cross-sectional study of long-stay nursing home residents aged ≥ 65 years with ADRD who were continuously enrolled in Medicare fee-for-service for 120 days before their annual assessment. We described usage by drug class and type and compared characteristics of users versus non-users overall and by potential indications: depression, anxiety, pain, and insomnia.

RESULTS: Among 232,543 residents with ADRD, 51.6% used antidepressants. Fewer than 5% had moderate or severe depressive symptoms (PHQ-9 ≥ 10). Use was highest among residents with depression or anxiety (69.5%), pain (61.9%), and insomnia (60.0%). Among those without these conditions, 14.1% were prescribed antidepressants. SSRIs were the most prescribed class (60.7%) overall. Citalopram, mirtazapine, sertraline, and trazodone were the most common medications. Residents with any current level of depression severity were more likely to use antidepressants compared to those without symptoms, whereas all levels of cognitive impairment were associated with lower use compared with cognitively intact residents with ADRD. Polypharmacy was strongly associated with increased use, while diabetes, heart failure, and stroke were associated with reduced use.

CONCLUSIONS: Antidepressants were frequently prescribed to residents with ADRD despite limited documentation of active depressive symptoms. Limitations in accurately capturing depressive symptoms in nursing home records, including underreporting by residents due to cognitive impairment and reliance on staff observation rather than self-report, may contribute to apparent discordance between symptoms and prescribing. Further research should evaluate treatment appropriateness, deprescribing opportunities, and risk-benefit balance of chronic treatment in this population.},
}

@article {pmid42082519,
year = {2026},
author = {Wang, J and Mao, Y and Liu, X and Hao, W and , },
title = {Learning patient-specific spatial biomarker dynamics via operator learning for Alzheimer's disease progression.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00719-x},
pmid = {42082519},
issn = {2056-7189},
support = {1R35GM146894/GM/NIGMS NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized future biomarker states remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.},
}

@article {pmid42082800,
year = {2026},
author = {Nazli, D and Poyraz, YK and Can, K and Ipekgil, D and Cakmak, N and Turhanlar-Sahin, E and Hacoglu, S and Erdost, HA and Iyilikci, L and Ozhan, G},
title = {Dexmedetomidine Exerts Multi-level Effects to Ameliorate Alzheimer's Disease Pathology in the Adult Zebrafish Brain.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42082800},
issn = {1559-1182},
mesh = {Animals ; Zebrafish ; *Dexmedetomidine/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Brain/pathology/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *Aging/pathology/drug effects ; Behavior, Animal/drug effects ; Peptide Fragments ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative condition involving β-amyloid (Aβ) deposition, tau abnormalities, neuroinflammation, neuronal degeneration, and progressive impairment of cognitive functions. Despite extensive research, effective disease-modifying therapies remain limited, highlighting the need for translationally relevant models and repurposable therapeutic candidates. Dexmedetomidine (DEX), an α2-adrenergic receptor agonist with known neuroprotective properties, was investigated in an adult zebrafish model of AD established through cerebroventricular administration of Aβ42. DEX treatment significantly reduced Aβ accumulation and was associated with reduced amyloidogenic gene expression, indicating transcriptional changes in amyloidogenic pathway-related genes. DEX attenuated neuroinflammation by reducing glial activation, lowering pro-inflammatory cytokine gene expression, and increasing expression of the anti-inflammatory gene il10. Immunofluorescence assessment further demonstrated reduced astrogliosis and preserved neuronal marker integrity, as indicated by increased HuC/D levels. Interestingly, DEX attenuated Aβ-induced proliferative responses, characterized by decreased PCNA expression, while enhancing cleaved caspase-3 levels, suggesting changes in proliferation and apoptotic signaling under Aβ stress conditions. Behavioral assessments further demonstrated that DEX alleviated Aβ42-induced anxiety- and aggression-like behaviors, improving behavioral phenotypes in this model. Overall, these findings underscore the multi-level effects of DEX in modulating AD-related pathological features. As a clinically available agent, DEX represents a promising candidate for repurposing in neurodegenerative disease contexts. Further preclinical studies in mammalian models are warranted to validate its translational relevance and therapeutic potential.},
}

Animals
Zebrafish
*Dexmedetomidine/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/pathology/genetics
*Brain/pathology/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Disease Models, Animal
*Aging/pathology/drug effects
Behavior, Animal/drug effects
Peptide Fragments

@article {pmid42082802,
year = {2026},
author = {Motieiyan, E and Motahari, R and Aliabadi, A and Khaksar, S and Abdolmaleki, S},
title = {Cobalt complexes in biology and medicine: enzymatic functions, pharmacological applications, and health challenges.},
journal = {Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry},
volume = {},
number = {},
pages = {},
pmid = {42082802},
issn = {1432-1327},
abstract = {Cobalt is an essential trace element in biochemistry that plays a crucial role in the structure and function of several important biomolecules. In this review, vitamin B12 is discussed as one of the best-known examples in this area. Various forms of this vitamin, including methylcobalamin and adenosylcobalamin, play a crucial role in metabolic reactions in mammals and prokaryotes. It also discusses cobalt-containing enzymes that are essential for various biological processes. These enzymes are B12-dependent enzymes, which are well studied, and cobalt-containing enzymes, which are less well known, such as methionine aminopeptidase, nitrile hydratase, glucose isomerase, and prolidase. In addition to the significant role of cobalt complexes in biochemistry, these complexes are considered potent anticancer agents that can exert their antiproliferative effects through the production of ROS, cell cycle arrest, MMP breakdown, and induction of apoptosis in cancer cells. Cobalt complexes are also being explained here for their antimicrobial properties against a variety of pathogens, including bacteria, fungi, and viruses. Furthermore, examples of these complexes are presented as promising agents for the suppression of AD, which could be effective by binding to Aβ-peptides and preventing their aggregation, which is a central feature of the pathogenesis of AD, or by combating the oxidative damage associated with the disease, or even by interfering with the enzyme activities associated with this disease. Finally, the challenges related to the toxicity of cobalt and its compounds in medicine are discussed, and chelation therapy is considered an effective treatment for cobalt poisoning.},
}

@article {pmid42082835,
year = {2026},
author = {Zheng, X and Chen, P and Li, D and Li, W and Liao, J and Zhang, M},
title = {Lamotrigine Improves Spatial Learning and Attenuates AD-Related Pathology in APP/PS1 Mice, with Possible Involvement of the cAMP/PKA/CREB Pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42082835},
issn = {1573-6903},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Lamotrigine/pharmacology/therapeutic use ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Spatial Learning/drug effects ; Mice, Transgenic ; Mice ; Presenilin-1/genetics ; Cyclic AMP Response Element-Binding Protein/metabolism ; Signal Transduction/drug effects ; Cyclic AMP/metabolism ; Male ; Brain/drug effects/metabolism/pathology ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by impaired spatial learning functions, amyloid-β accumulation, tau hyperphosphorylation, and neuroinflammation. Antiepileptic drugs such as lamotrigine have shown promise in improving brain functions in AD, but the underlying mechanisms remain unclear. This study aimed to evaluate the therapeutic effects of lamotrigine in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice and elucidate the underlying molecular mechanisms using integrated transcriptomic and metabolomic analyses. APP/PS1 mice were treated with lamotrigine from 3 months of age, and spatial learning performance was assessed using the Morris water maze test. Histological and molecular changes were evaluated through hematoxylin and eosin staining, Western blotting, ELISA, and immunohistochemistry. High-throughput RNA sequencing and untargeted metabolomics were performed to explore differentially expressed genes, metabolites, and enriched signaling pathways. Western blot validation and pharmacological inhibition were used to verify pathway involvement. Lamotrigine treatment significantly improved spatial learning performance, ameliorated neuronal degeneration, and decreased Aβ1 levels and tau phosphorylation in the brains of APP/PS1 mice. Inflammatory markers and glial activation were also markedly suppressed. Multi-omics analysis revealed alterations in key pathways related to synaptic plasticity, lipid metabolism, and autophagy. Notably, both omics data and protein validation highlighted the cAMP/PKA/CREB pathway as a potentially relevant pathway. Co-administration of the PKA inhibitor H89 abolished lamotrigine-induced upregulation of p-CREB and BDNF, supporting the involvement of this pathway. Lamotrigine improves spatial learning and attenuates AD-related pathology in APP/PS1 mice, possibly through modulation of the cAMP/PKA/CREB signaling pathway, highlighting its potential as a candidate for further investigation.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
*Lamotrigine/pharmacology/therapeutic use
Cyclic AMP-Dependent Protein Kinases/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
*Spatial Learning/drug effects
Mice, Transgenic
Mice
Presenilin-1/genetics
Cyclic AMP Response Element-Binding Protein/metabolism
Signal Transduction/drug effects
Cyclic AMP/metabolism
Male
Brain/drug effects/metabolism/pathology
Maze Learning/drug effects

@article {pmid42082960,
year = {2026},
author = {Liu, S and Zhu, J and Zhong, H and Zhou, D and Long, Q and Zhang, Z and Yang, X and Wu, Q and Cheng, C and Wu, J and Luu, HN and Wang, J and Zhao, B and Wu, C and Deng, Y and Wu, L},
title = {Investigating causal associations among inflammatory proteins, blood metabolites, and Alzheimer's disease risk.},
journal = {BMC psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12888-026-08136-4},
pmid = {42082960},
issn = {1471-244X},
abstract = {Alzheimer's disease (AD) is a prevalent degenerative neurological disorder with limited treatment options. Prior studies reported specific metabolites and inflammatory proteins to be related to AD risk. However, the intricate relationship between inflammatory proteins, blood metabolites, and AD risk in European population remains unclear. Genetic instruments for 1,091 metabolites and 736 inflammatory proteins were derived from two recent comprehensive genome-wide association studies. Univariable Mendelian Randomization was employed to assess potential causal effects of metabolites on AD risk, potential effects of inflammatory proteins on metabolites, and effects of inflammatory proteins on AD risk. Multivariable MR (MVMR) was further applied to disentangle direct effects of proteins and metabolites on AD. Twelve metabolites were identified to be associated with AD risk, and 226 inflammatory proteins demonstrated likely to be causal effects on these 12 metabolites. Further examining the associations between such inflammatory proteins and AD risk revealed 22 associations for which the effect directions from inflammatory proteins to metabolites, from metabolites to AD risk, and from inflammatory proteins to AD risk were aligned, suggesting inflammatory protein - metabolite - AD risk pathway. MVMR further highlighted four trios in which the effect directions were consistent with the UVMR results, supporting a metabolite‑mediated pattern. This large‑scale genetic analysis highlights specific metabolites as direct contributors to AD risk and suggests that certain inflammatory proteins may influence AD primarily through downstream metabolic pathways. Our findings offer potential novel therapeutic targets for AD intervention.},
}

@article {pmid42083360,
year = {2026},
author = {Pandey, H and Kaur, A and Khan, J and Sharma, A},
title = {Nanomedicine for Alzheimer's Disease: Diagnostic and Therapeutic Progress.},
journal = {MicroRNA (Shariqah, United Arab Emirates)},
volume = {},
number = {},
pages = {},
doi = {10.2174/0122115366427696260203074113},
pmid = {42083360},
issn = {2211-5374},
abstract = {The complex nature of the pathophysiology and limited treatment options of AD make it a huge challenge in healthcare. The recent developments in nanotechnology have given fresh hope for diagnosing and treating AD, which could serve as a way out of the existing problems. This review dwells on the role of nanotechnology in AD and its applications at its early stages through the development of nanosensors and boost imaging methods. Additionally, nanotechnology-driven therapeutic strategies are being investigated with nanoparticle-based drug delivery systems that aim to target the blood-brain barrier, among others. Current research innovations, clinical trials, and prospects highlight the transformative potential of nanotechnology in reshaping AD management. Ethical issues related to applying nanomedicine in neurodegenerative diseases, as well as fears about nanoparticles, are carefully analyzed herein. Finally, this review concludes with a synthesis of how nanotechnology has affected Alzheimer's Disease (AD) while emphasizing emerging trends and future directions toward advancing research on Alzheimer's Disease (AD). This comprehensive overview underscores the pivotal role of nanotechnology in revolutionizing AD prognosis and therapy, paving the way for personalized and effective treatment strategies.},
}

@article {pmid42083572,
year = {2026},
author = {Minhas, AM and Khan, AU and Gul Qazi, N and Nadeem, H and Ali, F},
title = {Pharmacological investigation of oxadiazole derivatives in Alzheimer's disease: Modulation of oxidative stress, neuroinflammation, and iNOS signaling.},
journal = {Iranian journal of basic medical sciences},
volume = {29},
number = {3},
pages = {423-437},
pmid = {42083572},
issn = {2008-3866},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of amyloid-beta (Aβ) aggregates. Aβ peptides alter synaptic function and produce neuroinflammation. The neurotoxic mechanisms are also related to increases in the expression of iNOS (inducible nitric oxide synthase), resulting in further neuronal degeneration and memory impairment.

MATERIALS AND METHODS: In the current study, we assessed the in vivo effect of the 1,3,4-oxadiazole derivative 2-{[5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl] sulfanyl}-
N-(1,3-benzothiazol-2-yl) acetamide (MA) on spatial memory and inflammatory responses induced by AlCl3 administration in animals.

RESULTS: A notable improvement in memory function was observed in the AlCl3-induced group at 29[th] post-injection, following MA treatment (5, 10, and 20 mg/kg), as indicated by the behavioral analysis. This effect is correlated with decreases in inflammatory markers such as NFKƁ, IL-6/ß1, IFN-γ, TNϜ-α, and NO levels, as well as a reduction in expression of neurodegenerative markers: β-amyloid and p-tau (*P<0.05, **P<0.01, ***P<0.001 vs disease control). The results from our study suggested that MA significantly enhances the levels of glutathione, catalase, and glutathione S-transferase while decreasing the lipid peroxidation (LPO) in comparison to the disease control group, and also improves mitochondrial dysfunction. The effects are further enhanced when MA was used in combination with aminoguanidine (AG), an iNOS inhibitor. Molecular dynamics (MD) simulations, along with protein mRNA expression and iNOS western blotting, further supported the results of in vivo experiments.

CONCLUSION: Our study proposed that MA attenuated the cytokine release, decreased oxidative stress, and iNOS expression, leading to a decrease in neurodegeneration.},
}

@article {pmid42083945,
year = {2026},
author = {Kumar, D and Walhekar, V and Kasaragod, MS and Kini, S},
title = {Discovery of Novel Quinazoline Thiazole Uredio Analogs as Dual Inhibitors of GSK-3β and CK-1δ as Anti-Alzheimer's Agents: Catching Two Fish with One Net.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266378266251017045841},
pmid = {42083945},
issn = {1873-4294},
abstract = {INTRODUCTION: AD is a widespread and debilitating neurodegenerative disorder, and existing treatments have demonstrated limited efficacy, emphasizing the need for novel therapeutic strategies. This study focused on the design of drug-like molecules with enhanced efficacy and minimized side effects through the application of structure-based scaffold hopping and molecular hybridization strategies.

METHODS: Molecular docking was carried out on the Glide module, Molecular dynamics simulation of 500 ns was executed employing Desmond, and ADMET prediction was achieved by the QikProp modules of Schrodinger.

RESULTS: Through molecular docking studies targeting the GSK-3β and CK-1δ enzymes, the compounds VDK12 and VDK14 were identified as promising inhibitors, showing favorable interactions within the active sites of these proteins, with docking energies of -9.9 kcal/mol and -10.1 kcal/mol, respectively. Molecular dynamics simulations further revealed that the VDK12 and VDK14 complexes exhibited stable interactions within the active sites of GSK-3β and CK-1δ throughout a 500 ns simulation. Additionally, in silico ADMET analysis demonstrated that VDK1 exhibited an excellent human oral absorption rate of 91.349%, outperforming other compounds in the series.

DISCUSSION: Molecules as dual inhibitors were designed successfully by the application of scaffold hopping and molecular hybridization. Designed molecules demonstrated excellent molecular docking and dynamics simulation results with an appropriate ADMET profile.

CONCLUSION: These findings strongly suggest the potential of VDK12 and VDK14 as dual inhibitors of GSK-3β and CK-1δ, offering a promising foundation for the development of new lead compounds for AD treatment.},
}

@article {pmid42083963,
year = {2026},
author = {Kanojia, N and Deswal, G and Grewal, AS and Kumar, J and Thapa, K and Sharma, A and Sharma, A and Dheer, D and Puri, V and Rani, L and Saini, V},
title = {Advances in Microneedle Technology for Targeted Therapy in Alzheimer's and Parkinson's Disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672018425956260117232402},
pmid = {42083963},
issn = {1875-5704},
abstract = {INTRODUCTION: The fourth major cause of death worldwide is Neurodegenerative Diseases (NDs), including Alzheimer's and Parkinson's disease. The existing therapies have only a small effect on alleviating symptoms, mainly because the therapeutic agents are difficult to cross the bloodbrain barrier. The purpose of the review is to discuss the potential of microneedle-based transdermal delivery systems to improve the delivery of drugs to the central nervous system and thereby manage neurodegenerative diseases effectively.

METHODS: The article summarizes and synthesizes the available literature that targets the strategies of microneedle-mediated drug delivery. The literature on the design, composition, pharmacokinetics, and mechanistic benefits of different microneedle platforms for surmounting central nervous system barriers was identified and thematically synthesized.

RESULTS: Microneedle systems have emerged as non-invasive delivery systems with the potential for localized and sustained drug delivery, overcoming the stratum corneum and the blood-brain barrier. Micro-needles can be used to deliver small molecules, peptides, and nanoparticles to the brain, thereby avoiding systemic side effects and enhancing drug bioavailability. Some of those designs include dissolving, coated, hollow, hydrogel-forming, and stimuli-responsive microneedles, which have been shown to target the brain and exhibit higher therapeutic efficiency in preclinical models.

DISCUSSION: Although technological advances have improved, the clinical translation of microneedlebased strategies remains limited. The future directions could include using microneedles with stem cell-based therapies, CRISPR/Cas9 gene editing, artificial intelligence-based delivery systems, and responsive release technology to facilitate customized treatment.

CONCLUSION: The Microneedle-based drug delivery systems are promising in overcoming the current limitations in the treatment of neurodegenerative diseases. Nonetheless, a large-scale clinical validation is necessary to guarantee safety, efficacy, and scalability to be applied to real-life scenarios.},
}

@article {pmid42068226,
year = {2026},
author = {Stites, SD and Kuz, C and Largent, EA and Harkins, K and Krieger, A and Sankar, P and Barber, SJ},
title = {Four Common Beliefs About Patient Memory Evaluations: Who Has Them and What Modifies Them?.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261447038},
doi = {10.1177/15333175261447038},
pmid = {42068226},
issn = {1938-2731},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/psychology ; Aged ; Middle Aged ; Adult ; *Health Knowledge, Attitudes, Practice/ethnology ; *Aging/psychology ; Aged, 80 and over ; },
abstract = {Understanding public beliefs about patients at memory centers may inform efforts to promote early diagnosis and guide clinical discussions of Alzheimer's disease (AD). Adults (N=3,527) read a vignette describing a fictional person at a memory center and rated the person's condition as a mental illness, part of typical aging, and psychological or biological origins. Vignettes varied by AD biomarker result, symptom stage, and treatment availability. Participants most strongly believed that the condition was part of typical aging and biological in origin, though beliefs varied across subgroups. Black and Asian participants reported stronger beliefs than White participants that the condition was a mental illness (β=0.39, P<0.001) and psychological (β=0.46, P<0.001). Men reported stronger beliefs that the condition was a mental illness (β=0.19, P<0.001), psychological (β=0.14, P<0.001), and part of typical aging (β=-0.08, P=0.04). Biomarker positivity heightened biological and lowered psychological attributions (all P<0.05). The findings offer specific insights to guide intervention.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/psychology
Aged
Middle Aged
Adult
*Health Knowledge, Attitudes, Practice/ethnology
*Aging/psychology
Aged, 80 and over

@article {pmid42068460,
year = {2026},
author = {Chen, JH and Tsai, TF},
title = {A Narrative Review: Do Systemic Drugs Used in the Treatment of Psoriatic Disease Affect Alzheimer's Disease?.},
journal = {Dermatology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42068460},
issn = {2193-8210},
abstract = {Various comorbidities have been associated with psoriasis. Most clinical studies support the hypothesis that psoriasis may be a risk factor for dementia. Meanwhile, some evidence indicates that certain immunomodulatory agents, many of which are widely used in psoriatic disease management, exert neuroprotective effects and may attenuate dementia progression. In view of the lack of existing studies that specifically investigate the effects of systemic treatments for psoriatic disease on dementia or cognitive impairment, in this narrative review, we focus on Alzheimer's disease, as a model to explore whether systemic psoriasis treatments influence dementia risk and severity. Our findings suggest that some systemic treatments for psoriasis may also provide potential neuroprotective benefits.},
}

@article {pmid42071065,
year = {2026},
author = {Fikry, H and Sadek, DR and Saleh, LA and Hasanin, MTM and Alkhalek, HAA},
title = {Dual protective role of curcumin- encapsulated chitosan nanoparticles against gastric and neural injury in a rat model of gut-brain axis dysfunction: a histological and biochemical study.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {42071065},
issn = {1432-1912},
abstract = {Gastric ulcer (GU) and Alzheimer's disease (AD) are prevalent age-associated disorders frequently accompanied by systemic oxidative stress and inflammation. Emerging evidence suggests that gastrointestinal dysfunction and inflammatory signaling may aggravate neurodegenerative processes. Curcumin (Cur) exhibits well-established antioxidant, anti-inflammatory, neuroprotective, and gastroprotective properties; however, its therapeutic utility is limited by poor bioavailability. The present study aimed to formulate and characterize Curcumin- encapsulated chitosan nanoparticles (Cur-CSNPs) and evaluate their dual protective effects in a clinically relevant comorbid rat model combining scopolamine-induced AD-like pathology and ethanol-induced GU. Male Wistar rats were divided into six groups: control, Cur-CS-NPs alone, GU, AD, GU + AD, and GU + AD treated with Cur-CSNPs. Behavioral assessments, biochemical analyses, histopathological evaluation, and immunohistochemical investigations were performed on brain and gastric tissues. GU + AD rats exhibited cognitive deficits, neuronal degeneration, amyloid-β accumulation, astrocyte activation, gastric mucosal injury, increased oxidative stress, NF-κB activation, elevated inflammatory cytokines, and enhanced apoptotic signaling. Cur-CSNP treatment significantly improved cognitive performance, reduced oxidative stress and inflammation, suppressed NF-κB signaling, decreased amyloid-β deposition, inhibited apoptosis, and restored gastric mucosal integrity. In conclusion, Cur-CSNPs exert concurrent neuroprotective and gastroprotective effects in a comorbid AD and GU model through coordinated modulation of oxidative stress, inflammation, amyloidogenic activity, and apoptotic pathways. These findings demonstrate that Cur-CSNPs exert dual neuroprotective and gastroprotective effects by modulating oxidative stress, inflammation, amyloidogenic pathways, and apoptosis, highlighting nano-curcumin as a promising therapeutic strategy for gut-brain axis-related disorders. Further investigations are warranted to elucidate the detailed molecular mechanisms and to explore the clinical applicability of nano-formulated curcumin as a therapeutic strategy for disorders involving concurrent gastrointestinal and neurodegenerative pathology.},
}

@article {pmid42071257,
year = {2026},
author = {Richard, JE and Mohammad, A and Lieblich, SE and Go, KA and Wang, S and Rechlin, RK and Splinter, TFL and Barreto, GE and Galea, LAM},
title = {Reproductive history differentially shapes the neural response of middle-aged hAPOEɛ4 female rats to estradiol therapy after a metabolic challenge.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00911-y},
pmid = {42071257},
issn = {2042-6410},
support = {PJT173554/CAPMC/CIHR/Canada ; },
abstract = {BACKGROUND: Advancing age, the APOEɛ4 allele, and female sex are the top nonmodifiable risk factors for Alzheimer's disease (AD). Female-specific experiences, such as parity and hormone therapy (HT) affect aging biomarkers such as metabolism and immune signaling, and may affect AD risk. Estradiol (E2), a component of many HTs, affects cognition and brain health in aging females although studies suggest the effects can vary depending on parity, genotype, and metabolic status which may account for some of the inconsistencies in the literature. We hypothesized that prior parity influences brain and metabolic health, including response to E2, depending on APOE genotype.

METHODS: Middle-aged female (10 month) wildtype (WT) or humanized (h) APOEɛ4 expressing rats, with different reproductive experience (nulliparous or primiparous) were fed a Western (WD) or standard diet (SD) for 2 months. In the second month, rats were given E2 or vehicle (oil) injections daily. Fear associative learning, plasma metabolic hormones, hippocampal inflammatory cytokine expression, and neuroplasticity (neurogenesis, synaptic protein) were assessed.

RESULTS: Females fed a WD gained weight and displayed metabolic dysregulation, regardless of genotype. E2 treatment reduced WD-induced weight gain and reduced metabolic hormones, with stronger effects in WT rats. E2 treatment increased dorsal hippocampal inflammatory cytokine expression selectively in primiparous hAPOEɛ4 females fed a WD. Previous parity increased neurogenesis and reduced certain cytokine expression in the hippocampus of middle-aged WT rats under a SD. Both E2 treatment and previous parity decreased dorsal neurogenesis in hippocampus of hAPOEɛ4 rats. In hAPOEɛ4 females, higher weight was associated with reduced contextual fear memory, an effect driven by primiparous females. In the cued fear conditioning task, hAPOEɛ4 females displayed better cued fear memory than WT, however, WD exposure reduced cued fear memory only in this group. Together, this indicates that diet and weight gain may be more detrimental to associative memory in hAPOEɛ4 females and that E2 treatment has more favourable outcomes in WT rats.

CONCLUSIONS: Previous parity alters how females respond to E2 and metabolic stress in midlife. Primiparous hAPOEɛ4 females were especially vulnerable to the effects of WD and E2, exhibiting more inflammation, impaired memory, and reduced weight-loss. These findings highlight the importance of considering parity and genotype when evaluating midlife metabolic and cognitive risk.},
}

@article {pmid42071824,
year = {2026},
author = {Li, Q and Jing, S and Li, N and Yuan, X and Wang, T},
title = {Causality relationship between 91 inflammatory factors and Alzheimer disease: A bidirectional Mendelian randomization study.},
journal = {Medicine},
volume = {105},
number = {17},
pages = {e48136},
doi = {10.1097/MD.0000000000048136},
pmid = {42071824},
issn = {1536-5964},
support = {2024439//Chengdu Medical Research Project/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/blood ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; *Inflammation/genetics/blood ; Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder characterized by amyloid plaque deposition, neurofibrillary tangles, and chronic neuroinflammation. Due to its complexity and difficult-to-treat nature, it has cast a huge shadow over global health. In addition to genetic susceptibility, the development of AD is closely related to systemic inflammation. This study aims to evaluate the association between systemic inflammatory factors and AD through a bidirectional Mendelian randomization (MR) design. Our MR design incorporated aggregated data from extensive genome-wide association studies to investigate the causal relationship between genetically determined systemic inflammatory factors and AD. The MR analysis results identified 9 potential systemic inflammatory regulatory factors: C-X-C motif chemokine 5, interleukin-18 receptor 1, interleukin-6, and tumor necrosis factor, which were associated with an increased risk. Conversely, AD is significantly correlated with 5 circulating inflammatory regulatory factors, namely, tumor necrosis factor-related apoptosis-inducing ligand, stem cell factor, monocyte chemoattractant protein-4, interleukin-5, and cystatin D, which are considered downstream consequences of AD. It is worth noting that our results have, for the first time, clarified the significant roles of inflammatory factors such as cystatin D and monocyte chemoattractant protein-4 in AD, providing new markers and key targets for further exploration of the molecular mechanism and clinical diagnosis and treatment of AD.},
}

Humans
*Alzheimer Disease/genetics/blood
Mendelian Randomization Analysis
Genome-Wide Association Study
*Inflammation/genetics/blood
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide

@article {pmid42072160,
year = {2026},
author = {Tng, TJW and Cheah, IK and Halliwell, B and Lim, KL},
title = {Potential Protection Against Parkinson's Disease by Ergothioneine-Nature's Multifactorial Neuroprotectant.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {4},
pages = {},
doi = {10.3390/antiox15040519},
pmid = {42072160},
issn = {2076-3921},
support = {#023643-00001//Ministry of Education/ ; },
abstract = {The use of neuroprotective nutraceuticals as a strategy against neurodegenerative diseases such as Parkinson's disease (PD) has gained considerable traction in recent years. In this review, we highlight ergothioneine (ET)-a naturally occurring thiol/thione derivative abundant in mushrooms-as a promising candidate, given its long half-life, blood-brain barrier penetration, and high bioavailability. Numerous population studies have linked low blood ET levels with increased risk and progression of neurological and other age-related disorders in humans, suggesting that dietary ET may confer neuroprotective benefits. Supporting this, several studies have demonstrated the efficacy of ET treatment in reducing PD-associated molecular damage across various pre-clinical models such as C. elegans, Drosophila, rodent models and human neuronal cultures, leading to marked improvements in disease phenotypes. Here, we summarize some of the proposed mechanisms by which ET may exert neuroprotection in PD, including the reduction of protein aggregation, enhancement of mitochondrial function, mitigation of oxidative stress, and attenuation of apoptosis and neuroinflammation. We also highlight recent clinical trials demonstrating the safety and potential efficacy of ET and propose future research to facilitate the translation of ET into the clinic.},
}

@article {pmid42072570,
year = {2026},
author = {Dong, L},
title = {A Unified Information Bottleneck Framework for Multimodal Biomedical Machine Learning.},
journal = {Entropy (Basel, Switzerland)},
volume = {28},
number = {4},
pages = {},
doi = {10.3390/e28040445},
pmid = {42072570},
issn = {1099-4300},
support = {R01CA309499/CA/NCI NIH HHS/United States ; },
abstract = {Multimodal biomedical machine learning increasingly integrates heterogeneous data sources (including medical imaging, multi-omics profiles, electronic health records, and wearable sensor signals) to support clinical diagnosis, prognosis, and treatment response prediction. Despite strong empirical performance, most existing multimodal systems lack a principled theoretical foundation for understanding why fusion improves prediction, how information is distributed across modalities, and when models can be trusted under incomplete or shifting data. This paper develops a unified information-theoretic framework that formalizes multimodal biomedical learning as an information optimization problem. We formulate multimodal representation learning through the information bottleneck principle, deriving a variational objective that balances predictive sufficiency against informational compression in an architecture-agnostic manner. Building on this foundation, we introduce information-theoretic tools for decomposing modality contributions via conditional mutual information, quantifying redundancy and synergy, and diagnosing fusion collapse. We further show that robustness to missing modalities can be cast as an information consistency problem and extend the framework to longitudinal disease modeling through transfer entropy and sequential information bottleneck objectives. Applications to multimodal foundation models, uncertainty quantification, calibration, and out-of-distribution detection are developed. Empirical case studies across three biomedical datasets (TCGA breast cancer multi-omics, TCGA glioma clinical-plus-molecular data, and OASIS-2 longitudinal Alzheimer's data) show that the framework's key quantities are computable and interpretable on real data: MI decomposition identifies modality dominance and redundancy; the VMIB traces a compression-prediction tradeoff in the information plane; entropy-based selective prediction raises accuracy from 0.787 to 0.939 at 50% coverage; transfer entropy reveals stage-dependent modality influence in disease progression; and pretraining/adaptation diagnostics distinguish efficient from wasteful fine-tuning strategies. Together, these results develop entropy and mutual information as organizing principles for the design, analysis, and evaluation of multimodal biomedical AI systems.},
}